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Matrix metalloproteinases and their multiple roles in neurodegenerative diseases

Gary A Rosenberg

Matrix metalloproteinases (MMPs) and proteins containing a disintegrin and metalloproteinase domain (ADAM) are important in neuroinflammation, and recent studies have linked their actions to neurodegenerative disorders. MMPs act as cell-surface sheddases and can affect cell signalling initiated by growth factors or death receptors. Four tissue inhibitors of metalloproteinases (TIMPs) regulate metalloproteinase activity. These proteases increase the permeability of the blood­brain barrier, which can cause oedema, haemorrhage, and cell death. MMPs also participate in tissue repair by promoting angiogenesis and neurogenesis. In vascular cognitive impairment, MMPs change permeability of the blood­brain barrier and might contribute to white matter damage. MMPs and ADAMs might contribute to the formation and degradation of amyloid proteins in Alzheimer's disease and cause death of dopaminergic neurons in Parkinson's disease. In this Review, by examining the effects of neuroinflammation, we try to understand the role that MMPs might have in neurodegenerative diseases. Therapeutic strategies that use inhibitors of MMPs could represent potential novel treatments for neurological diseases.

Lancet Neurol 2009; 8: 205­16 Departments of Neurology, Neurosciences, and Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA (G A Rosenberg MD) Correspondence to: Gary A Rosenberg, Health Sciences Center, Department of Neurology, MSC 10 5620, 1 University of New Mexico, Albuquerque, New Mexico 87131-0001, USA [email protected]

Introduction

Metalloproteinases are a large family of important proteases that include matrix metalloproteinases (MMPs) and proteins with a disintegrin and metalloproteinase domain (ADAM).1 A major role of MMPs is that of sheddases at the cell surface, where they control activation of growth factors, death receptors, and other signalling molecules. These enzymes are produced in a latent form but, once activated, regulate many physiological and pathological processes. Among these processes, MMPs increase the permeability of the blood­brain barrier as part of the neuroinflammatory response in hypoxia­ischaemia, multiple sclerosis, and infection.2 MMPs cause the increase in permeability of the blood­brain barrier by attacking the extracellular matrix, basal lamina, and tight junctions in endothelial cells, resulting in the final common pathway downstream of acute neuroinflammatory damage. When acute hypoxia­ ischaemia initiates the cellular damage, MMPs target the matrix proteins of blood vessels and brain cells, resulting in cytotoxic and vasogenic oedema, haemorrhagic transformation, and apoptosis of neurons and oligodendrocytes. Neuroinflammation without hypoxia­ischaemia, as occurs in infection and immunological reactions, follows another pattern of MMP-induced injury: the blood vessel remains the main site of pathological changes with mainly vasogenic oedema (which increases the extracellular space) but, without hypoxia, neuronal cell death might not occur.3 Recent studies have also implicated MMPs in the chronic neurodegeneration associated with vascular cognitive impairment, Alzheimer's disease, and Parkinson's disease. Additionally, MMPs have key roles in tissue repair,4 for which they activate angiogenesis and neurogenesis. Several reviews have been published on MMPs, ADAMs, and tissue inhibitors of metalloproteinases (TIMPs) in acute neuroinflammation;1,2,4 however, a comprehensive discussion of the emerging role of MMPs and ADAMs in neurodegeneration is not available. Therefore, their role in neurodegenerative diseases is discussed in this Review.

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Metalloproteinase structure, activation, and inhibitors

MMPs

MMPs share a common structure that comprises four main domains: the propeptide, catalytic, haemopexin-like, and transmembrane domains (figure 1).5 The propeptide domain contains a cysteine residue that binds zinc in the active site to form the cysteine switch. The binding of cysteine in the catalytic domain blocks the active zinc site, maintaining the latent or inactive state.6 Although there is continuous production of constitutively expressed MMPs and ADAMs, the proteins remain latent until they are activated by free radicals or enzymes that free the cysteine bond or cleave the propeptide region. Most MMPs, with the exception of the membrane-type MMPs (MT-MMPs), are secreted and act in the extracellular space. An intracellular role for MMP3 (also known as stromelysin-1) in cell death of dopaminergic neurons has been recently identified.7 MMPs are divided into four main subgroups on the basis of domain structure: collagenases, gelatinases, stromelysins, and MT-MMPs. Collagenases degrade triplehelical fibrillar collagens, which are the main components of bone and cartilage. In the brain, gelatinase A (MMP2) and gelatinase B (MMP9) have been the most intensively studied because of the ease with which they can be identified by gelatin zymography and their prominent role in injury and repair. Gelatinases degrade molecules in the basal lamina around capillaries, facilitate angiogenesis and neurogenesis, and contribute to instigating cell death (table 1). Stromelysins (MMP3, MMP10, MMP11, and MMP7 [also known as matrilysin]) are small proteases that degrade components of the extracellular matrix, although not the triple-helical fibrillar collagens. MT-MMPs contain a furin cleavage site near the propeptide region and are activated intracellularly by the proconvertase furin, and the serine protease plasmin. MT-MMPs are membrane bound and act at the cell surface as sheddases with several important functions, including activation of other proteases and growth factors.

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A

Signal peptide Propeptide Furin cleavage site FN binding site Ca2+ Zn2+ Ca2+ HP domain TMD

B

C/EBP NF-B ISE 1 ISE 2 TCF CIZ TIE AP1 PEA3 AP1 STAT TATA MMP1

Hinge region

p53

AP2

PEA3

PEA3

CREB

PEA3

SP1

SP1

AP2

MMP2

Catalytic domain Pre-Pro Zn2+ Matrilysin (MMP7) Stromelysins (MMP3, MMP10, MMP11, and MMP13) HP TMD MMP14 NF-B Pre-Pro Zn2+ FN Hinge HP Gelatinases (MMP2 and MMP9) NF-B SP1 PEA3 AP1 TIE AP1 KRE RCE TATA MMP9 SPRE TCF CIZ PEA3 PEA3 TCF AP1 TBS AP1 TATA MMP3

ZBP

NF-B

Pre-Pro

Zn2+

Hinge

HP

CIZ

TIE

TIE

TIE

TCF

PEA3

PEA3

TCF

AP1

PEA3

TATA

MMP7

Pre-Pro

Furin

Zn2+

Hinge

C/EBP

C/EBP

PEA3

PEA3

PEA3

C/EBP

C/EBP

EGR1

SP1

MMP14

Figure 1: MMP protein structure and binding sites on the promoters of the MMP genes (A) A signal peptide and the propeptide region form part of the cysteine switch, which folds over the zinc in the catalytic site and maintains a latent state. A cleavage site enables the proconvertase furin to activate MMP by cleaving the propeptide. An FN binding site is present in MMP2 and MMP9, connecting them with the basal lamina. The catalytic zinc site is present in all MMPs. A haemopexin domain is joined to the catalytic site by the hinge region. MMP14 (an MT-MMP) has a TMD. (B) MMP2 has AP2 and SP1 binding sites, which are found in promoter regions of constitutively expressed enzymes. MMP1, MMP3, MMP7, and MMP9 have AP1 binding sites, which are responsive to oncogenes and cytokines, consistent with their expression during inflammation. NF-B is another inflammatory binding site. Adapted from Overall and Lopez-Otin,5 with permission from Macmillan Publishers Ltd. AP=activator protein. C/EBP=CCAAT/enhancer-binding protein. CIZ=CAS-interacting zinc-finger protein. CREB=cyclic AMP response-element binding protein. EGR=early growth response site. FN=fibronectin. HP=haemopexin. ISE=immortalisation-sensitive element. KRE=keratinocyte differentiation-factor responsive element. MMP=matrix metalloproteinase. MT=membrane type. NF-B=nuclear factor-B. PEA=polyomavirus enhancer-A binding-protein. Pre-Pro=prepropeptide. RCE=retinoblastoma control element. SP=specificity protein. SPRE=stromelysin-1 platelet-derived growth factor responsive element. STAT=signal transducer and activator of transcription. TBS=translocation-ETS-leukaemia binding site. TCF=T-cell factor site. TIE=transforming growth factor inhibitory element. TMD=transmembrane domain. ZBP=zinc-binding protein.

As described above, MMPs are secreted as latent enzymes and require activation. Proteolysis is tightly regulated to prevent tissue damage. Products of a series of inducible genes, including MMP3 and MMP9, are normally present at low concentrations, but rapidly increase in quantity to inflammatory stimuli. The promoter regions of the inducible genes that encode MMPs generally contain binding sites for transcription factors such as activator protein (AP1) and nuclear factor-B (NF-B), which are responsive to oncogenes and cytokines (figure 1). MMP2 is constitutively expressed and found in healthy brain and cerebrospinal fluid. The MMP2 promoter region contains

Function Gelatinases (MMP2 and MMP9) Stromelysins (MMP3 and MMP10) and matrilysin (MMP7) Cause disruption of the blood­brain barrier, angiogenesis, neurogenesis, remodelling of the basal lamina, regeneration of axons, remyelination, and apoptosis Inhibitor All TIMPs

Cause proteolysis of proteins in the extracellular matrix, disruption of All TIMPs the blood­brain barrier, angiogenesis, synaptic remodelling, glutamate receptor proteolysis, and apoptosis TIMP3 TIMP1 TIMP3

MT-MMPs (MMP14, also Form trimolecular complex with TIMP2 and pro-MMP2 for activation known as MT1-MMP) of MMP2 at cell surface ADAM10 ADAM17 (TACE) Acts as -secretase in amyloid precursor protein proteolysis, degrades NOTCH, acts as sheddase at cell surface for growth factors and integrins

binding sites for AP2, specificity protein 1, and polyomavirus enhancer-A binding-protein 3 (figure 1).5 MMP2 is activated at the cell surface by membrane-bound MMP14 (MT1-MMP). Activation implicates formation of a trimolecular complex of pro-MMP2, TIMP2, and MMP14. By binding the complex to regions close to the membrane, MMP14 constrains the action of MMP2.8 Because MMP2 is constitutively expressed, this constraint controls the extent of damage to the extracellular matrix, whereas MMP3 and MMP9, which are secreted into the extracellular space where they can move around freely, cause more extensive damage to the injury site. MMP14 has an NF-B binding site, suggesting that this gene can also be induced during inflammation. Cytokines, such as tumour necrosis factor (TNF) and interleukin 1, induce transcription of MMP3 and MMP9, which is important in both acute and chronic neuroinflammation. In the case of MMP9, several activation mechanisms have been suggested, such as other proteases (eg, MMP3) and free radicals (eg, nitric oxide, which acts through N-nitrosylation).9,10

ADAMs

ADAMs are transmembrane proteins that bind to integrins and are important in intracellular signalling and cell adhesion.11 Although several of these metalloproteinases have been identified, only a few are known to have roles in the brain (table 1).12 The subunits of the ADAMs comprise a catalytic domain at the end of the extracellular extension,

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Acts as -secretase and sheddase for TNF receptors at the cell surface, TIMP3 produces 17-kDa TNF from the 28-kDa form

ADAM=a disintegrin and metalloproteinase. MMP=matrix metalloproteinase. MT=membrane type. TACE=TNF converting enzyme. TIMP=tissue inhibitor of metalloproteinases. TNF=tumour necrosis factor.

Table 1: Main metalloproteinases in the CNS and their endogenous inhibitors

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which is composed of three domains: a disintegrin, a cysteine-rich domain, and epidermal growth factor repeats. The cytoplasmic tail attached to the epidermal growth factor domain protrudes through the membrane and signals cell-surface events to the cytoplasm.4 The disintegrin domain binds to integrins whereas the cysteine-rich region interacts with proteoglycans. The catalytic region of the ADAM molecules releases bound proteins from the extracellular matrix and cell surface through a process called ectodomain shedding. Several important examples of the function of the ADAMs in the CNS include processing of amyloid precursor protein and transforming growth factor (TGF). ADAMs are implicated in cellular proliferation, migration, differentiation, and survival, as well as in axonal growth and myelination.1 For example, ADAM10 is possibly an -secretase that cleaves amyloid precursor protein (table 1);13 and ADAM17 (also known as TNF converting enzyme or TACE) activates TNF.14

Molecular weight (kDa) MMPs Other functions inhibited TIMP1 TIMP2 28 21 All MMPs ADAM10 All MMPs Strong inhibitor of MMP9 Forms trimolecular complex with proMMP2 and MMP14 (also known as MT1MMP) to activate MMP2 Apoptosis, inhibits angiogenesis

Location Secreted into the ECM Secreted into the ECM Bound to the ECM Secreted into the ECM

TIMP3

24 (unglycosylated) or 27 (glycosylated) 22

All MMPs ADAM10 ADAM17 All

TIMP4

Inhibits angiogenesis

ADAM=a disintegrin and metalloproteinase. ECM=extracellular matrix. MMP=matrix metalloproteinase. MT=membrane type. TIMP=tissue inhibitor of metalloproteinase. Adapted from Baker, Edwards, and Murphy.12

Table 2: Nomenclature, molecular weights, functions, and location of TIMPs

Apoptosis or cell survival

Apoptosis or cell survival

TIMPs

TIMPs are small proteins with molecular weights between 21 and 28 kDa; these enzymes are codified by highly conserved genes and have overlapping functions (table 2). So far, four TIMPs have been identified.15 TIMPs have inhibitory actions against most MMPs with some predilections: TIMP1 mainly inhibits MMP9, whereas TIMP2 inhibits MMP2 and, paradoxically, contributes to activation of pro-MMP2. TIMP3 is the only TIMP bound to the extracellular matrix.16 TIMP3 inhibits several membrane-bound molecules with sheddase functions, such as MMP14, MMP3, and TACE, indicating that TIMP3 plays a central part in several important reactions, including cellular growth, cellular death, and tissue repair (figure 2).2 TIMP3 is expressed early after ischaemia and contributes to apoptosis of neurons in the middle cerebral artery suture occlusion model.17,18 TIMP3 mRNA is overexpressed in developing brain tissue and after injury in rats.19,20 Stimulation of cultured astrocytes by lipopolysaccharide leads to expression of TIMP3, which inhibits activation of MMP2 in neurons; decreased concentrations of active MMP2 protect the blood­brain barrier, but increased concentrations of TIMP3 could promote cell death.21 Although a fourth TIMP has been identified,15 the function of this protein in the brain is unknown.

mFas/FasL

sFasL/sFas

mTNF/mTNFR1

sTNF/sTNFR1

MMP3

TACE

MMP9

pro-MMP9

TIMP3

mAPP

sAPP

BBB disruption

MT-MMP

VEGFR2

Amyloid deposition

MMP2

pro-MMP2

Angiogenesis

Neuroinflammation

CNS injury initiates a cascade of events that have been broadly defined as neuroinflammation. This term is loosely applied to reactions in brain trauma, ischaemic injuries, immunological reactions, and infections. Generally, there is a cytokine and chemokine response associated with production of free radicals and proteases. Although similar mediators, such as TNF, interleukin 1, and chemokines, are implicated, tissue responses differ with the specific injury. Factors that affect the outcome of the inflammatory process include presence of hypoxia­ischaemia, duration of injury, presence of infection, and types of cells involved.

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Figure 2: The actions of TIMP3 TIMP3 is an inhibitor of MMP3, MT-MMP, TACE, and the vascular endothelial growth factor receptor 2. MMP3 activates MMP9, which leads to disruption of the BBB, but MMP3 also cleaves FasL from the cell surface, which protects the brain from apoptosis. MT-MMP activates MMP2, which also results in disruption of the BBB. When TIMP3 inhibits MMP3, it blocks the release of FasL, causing apoptosis, but it also disrupts the activation of MMP9, which blocks BBB opening. Permeability of the BBB is also affected by TIMP when it inhibits MT-MMP, and subsequently, MMP2 activation. TACE activates TNF to the soluble form. Additionally, TACE cleaves the TNF family death receptor p55TNFR1 making the inhibitory action of TIMP3 on TACE difficult to predict, particularly as this is dependent on the type of injury. Inhibition of the VEGFR2 by TIMP3 blocks angiogenesis. APP=amyloid precursor protein. BBB=blood­brain barrier. FasL=Fas ligand. mAPP=membrane-bound APP. mFas=membrane-bound Fas. mFasL=membrane-bound FasL. MMP=matrix metalloproteinase. MT=membrane type. mTNF=membrane-bound TNF. mTNFR=membrane-bound TNFR. sAPP=soluble APP. sFas=soluble Fas. sFasL=soluble FasL. sTNF=soluble TNF. sTNFR=soluble TNFR. TACE=TNF converting enzyme. TIMP=tissue inhibitor of metalloproteinases. TNF=tumour necrosis factor. TNFR=tumour necrosis factor receptor. VEGF=vascular endothelial growth factor. VEGFR=vascular endothelial growth factor receptor.

Inflammation without hypoxia

Cells that have not been exposed to hypoxia might survive inflammation initiated by immunological reactions or infection. In the absence of hypoxia, inflammation mainly attacks blood vessels because of leucocyte infiltration. Injury to vessels might enable extravasation of serum proteins, leading to vasogenic cerebral oedema. For example, in an acute exacerbation of multiple sclerosis, the immunological reaction is focused on the blood vessel and might not necessarily damage the surrounding cells.

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However, secondary to the damaged blood vessels, cells might die as toxins enter the brain or as intracranial pressure increases. Occasionally, inflammation leads to infarction and distinction between inflammation due to hypoxia­ischaemia and immunological factors is obscured. Additionally, chronic infections or immunological reactions can lead to neurodegeneration. Chronic inflammation activates microglia and triggers macrophages to repair the tissue. During the removal of debris and remodelling of the damaged regions, toxic proteases might be released and free radicals formed. When macrophages are recruited to regions with myelinated fibres, demyelination might result as a bystander effect. However, evidence for this effect is derived from in vitro studies of the effect of plasmin and MMPs on myelin proteins and needs confirmation in vivo.22,23

Acute neuroinflammation

Acute ischaemic injury causes excitotoxic cell death through release of glutamate, production of free radicals, and activation of endonucleases that destroy DNA in the nucleus. Although blood vessels are the target of all forms of inflammation in the brain, cell death is more prominent in ischaemic injury than in infection and immunological disorders. Duration of inflammatory response also affects response to injury. When macrophages are recruited to a chronic injury site they secrete proteases, which might cause sustained damage to surrounding tissue. This chronic response to injury might actually be interpreted as an attempt at tissue repair. Cerebral blood vessels have tight junctions and are surrounded by basal lamina, astrocytes, and neurons, forming the neurovascular unit.24 In hypoxia­ischaemia, the acute inflammatory process includes a final common pathway formed by free radicals and MMPs that attack proteins in tight junctions and components of the basal lamina, causing oedema, haemorrhage, and cell death.25 Loss of oxygen and energy substrates releases glutamate into the extracellular space, initiating molecular events in the injured cells that might result in loss of membrane integrity and necrosis.

decreased the damage to the blood­brain barrier and the infarct size.29 Cyclo-oxygenases are linked to the production of MMP9, possibly as part of the free-radical response, and inhibitors of cyclo-oxygenases restrict MMP9 production after intracerebral injection of TNF in rodents.30 MMP3 is an inducible enzyme and its concentration increases in hypoxia­ischaemia and immunological reactions.30,31 When Mmp3 is knocked out, the normal disruption of the blood­brain barrier that occurs after intracerebral injection of lipopolysaccharide is attenuated and Mmp3 knockout mice have fewer neutrophils recruited to the site of inflammation than do wild-type mice.32 Apoptotic cell death is dependent on cell-surface death receptors.2,18,33 When these receptors of the TNF family such as Fas and the TNF receptor 1 (p55TNF-R1; TNFR1) are bound to their ligands (FasL and TNF, respectively), apoptosis occurs. MMP3 cleaves FasL from the cell surface (cell culture studies indicate this is most probably from an adjacent neuron, although origination of FasL might be different in vivo2) and apoptosis is attenuated. However, neurons deprived of glucose and oxygen undergo TIMP3mediated apoptosis, in which TIMP3 prevents MMP3 from cleaving FasL from the cell surface.18,34­36 TACE cleaves latent TNF from the cell surface of macrophages or microglia, producing the mature, active 17-kDa form. This active TNF then binds TNFR1, promoting apoptosis. However, TACE can also release TNFR1 from the neuronal cell surface, most likely preventing apoptosis. TIMP3 inhibits TACE; therefore, inhibition of released active TNF attenuates cell death, whereas inhibition of TNFR1 shedding facilitates cell death. Because of the dual actions of TACE, the exact effect of inhibition by TIMP3 is difficult to predict. Figure 3 shows the possible roles of TIMP3 in neuronal cell death via Fas and TNFR1.

MMPs in autoimmune disorders and infection

In injury initiated by a hypoxic­ischaemic insult, death of neurons and astrocytes parallels that that occurs after blood vessel damage. By contrast, when the initiating event is immunological or an infectious pathogen, the main site of injury is blood vessels alone. Whenever the blood­brain barrier is affected, MMP9 is a key factor in the injury process. Exacerbation of acute multiple sclerosis causes an increase in MMP9 concentrations in cerebrospinal fluid.37 Treatment with high-dose prednisolone, which restores blood­brain barrier integrity during a multiple sclerosis episode, lowers MMP9 concentrations in cerebrospinal fluid.38 Indexing MMP9 concentrations in the cerebrospinal fluid and blood to albumin showed that the enzyme was produced endogenously.39 In experimental allergic encephalomyelitis, an animal model of multiple sclerosis, demyelinated regions are associated with inflammation around blood vessels in the brain and the spinal cord. Treatment of animals with the MMP inhibitor GM-6001 suppresses development of clinical experimental allergic encephalomyelitis in mice.40 Experimental allergic neuritis in rats, a model for Guillain-Barré syndrome, causes an

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MMPs in hypoxia­ischaemia

The basal lamina around cerebral blood vessels contains extracellular matrix proteins, including laminin, fibronectin, heparan sulphate, and type IV collagen. Proteolysis of the blood­brain barrier by MMPs results in loss of basal lamina proteins, which increases the risk of haemorrhage.26,27 MMP2, MMP3, and MMP9 increase the permeability of the blood­brain barrier. Inhibitors of MMPs can reduce damage to the blood­brain barrier.28 Mice that are deficient in superoxide dismutase have an extreme response to hypoxic­ischaemic insults and have greater damage to the blood­brain barrier than do wildtype mice. In ischaemia with reperfusion, MMPs are induced and disrupt the blood­brain barrier; for instance, in an Mmp9 knockout model, focal ischaemic lesions

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immunologically mediated attack on peripheral nerves that is associated with inflammation around blood vessels. Inflammatory cells recruited to the blood vessels in the nerves release MMPs that disrupt the blood­nerve barrier. In rats with experimental allergic neuritis, a broadspectrum MMP inhibitor, BB-1101, which also inhibits TACE, reduces damage to the nerves.41

Cleaved FasL Neuron ? TIMP3 TACE

Macrophage or microglia

Pro-TNF

Metalloproteinases in neurodegeneration

Evidence is emerging of long-term effects of MMPs in neurodegenerative diseases, including damage to white matter in patients with vascular cognitive impairment, degradation of amyloid peptides in Alzheimer's disease, and apoptosis of dopaminergic neurons in Parkinson's disease.

Extracellular matrix

FasL

MMP3 Active TNF

Fas

MMPs in vascular cognitive impairment

In vascular cognitive impairment, MMPs are induced by hypoxic hypoperfusion in the white matter; patients with vascular cognitive impairment express hypoxia-inducing factor 1 (HIF1) in brain tissues with white matter hyperintensities on MRI. During hypoxia, HIF1 increases, leading to expression of many genes implicated in injury and repair.42 Furin contributes to activation of MMPs implicated in injury. HIF1 also stimulates expression of the same substances that mediate repair, including vascular endothelial growth factor (VEGF) and TGF.43 Because hypoxia seems to play a crucial part in vascular cognitive impairment, an understanding of the role of HIF1 is important. For example, in a rat model of vascular cognitive impairment, hypoxic hypoperfusion induces MMPs and thus increases the permeability of the blood­brain barrier in the white matter.44 Microglia involved in remodelling of blood vessels damaged by hypertension and diabetes secrete proteases, including MMPs and plasmin or plasminogen activator. These proteases secondarily break down myelin basic protein in animal brain tissue in vitro, which might also be a mechanism for demyelination associated with vascular disease in human beings.22,23,45 Patients with vascular cognitive impairment can be classified into two groups, with some overlap: patients with large-vessel pathology or multi-infarct dementia and patients with small-vessel pathology or Binswanger's disease.46 Patients with Binswanger's disease have extensive white matter hyperintensities on MRI, which are thought to be caused by hypoxia­ischaemia (figure 4).47 These white matter changes are also seen in patients with Alzheimer's disease and in some healthy elderly people.46 Myelin is lost, but U-fibres and cortical cells are spared. In the small-vessel form with extensive white matter disease, the astrocytes are reactive in the white matter and oligodendrocytes are lost (figure 4). The blood vessels in the deep white matter are generally fibrotic or have fibrohyaline changes consistent with thickened basal lamina and damaged endothelial cells, which would contribute to the abnormalities in the blood­brain barrier (figure 4).

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Cytoplasm

DISC

TNFR1

DISC

Neuron

Caspase 8

Apoptosis

Figure 3: TIMP3-regulated mechanisms of apoptosis The death receptors Fas and TNFR1 are transmembrane proteins. The extrinsic pathway of apoptosis is initiated by the activation of caspase 8 when the ligands FasL and TNF bind their receptors. MMP3 activated during injury cleaves FasL from the cell surface of an adjacent cell, presumed to be a neuron.2 Released FasL does not bind Fas and apoptosis is prevented. However, TIMP3 inhibits MMP3 from shedding FasL, meaning that the apoptotic pathway is resumed. TACE can release mature TNF from macrophages or microglia cells, enabling TNF to bind to the TNFR1. TACE can also release TNFR1 from the cell surface. This dual action of TACE makes a prediction of the outcome difficult. TIMP3 blocks this release of TNFR1 from the cell surface, triggering apoptosis. TIMP3 also blocks the release of TNF (see text). DISC=death-inducing signalling complex. FasL=Fas ligand. MMP=matrix metalloproteinase. TACE=TNF converting enzyme. TIMP=tissue inhibitor of metalloproteinases. TNF=tumour necrosis factor . TNFR=tumour necrosis factor receptor.

When the white matter disease causes progressive symptoms such as gait instability, executive dysfunction, and incontinence, Binswanger's disease is suspected.48 The abnormal MRI signal in white matter is associated with cognitive decline in large population studies.49 Most of the patients with white matter changes have conditions that affect the small blood vessels, such as hypertension and diabetes. The deep white matter, which forms a watershed circulation (produced by the confluence of several end arteries that originate on the surface and that provide poor circulation to the deeper regions), is vulnerable to hypoxic events.43 In hypoxic tissue, MMP expression increases in different cell types. Patients with vascular cognitive impairment have high cerebrospinal fluid concentrations of MMP9, but patients with Alzheimer's disease do not.50 In human tissue obtained at autopsy in patients with vascular cognitive impairment, immunohistochemical staining with antibodies to MMPs showed increased expression in white matter, particularly around blood vessels in regions with loss of myelin.47

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Poor perfusion of the watershed regions in deep white matter might be the mechanism of damage.51 Hypertensive vascular disease and diabetes mellitus further reduce the perfusion of these vulnerable regions. Although development of animal models has been hampered by the heterogeneity of vascular cognitive impairment, the animal model most commonly used to study the hypoxic injury to the deep white matter is that of bilateral carotid artery occlusion in rats. This procedure results in damage to white matter that includes hypoxic hypoperfusion secondary to the permanent occlusion of both carotid

A B

C

D

E

F

Figure 4: MRI scan and histological samples from patients with small-vessel form of vascular cognitive impairment or Binswanger's disease (A) Fluid attenuated inversion recovery MRI scan showing extensive white matter lesions in the periventricular region. (B) Histological section from the white matter in a patient with Binswanger's disease shows extensive gliosis. The arrow shows an astrocyte immunostained with glial fibrillary acidic protein. (C) Fibrotic blood vessel surrounded by inflammatory macrophages. (D) Blood vessel exposed to long-term hypertension with damage to the bloodvessel wall and eosinophilic deposits. (E) Immunostaining with antibodies to MMP3 detects an immunoreactive astrocyte (arrow). (F) Immunostaining with antibodies to MMP3 detects an MMP3-positive macrophage around a fibrotic blood vessel in a demyelinated area (arrow). MMP=matrix metalloproteinase. A, C, and D are adapted from Rosenberg, Sullivan, and Esiri,47 with permission from Lippincott Williams & Wilkins. B was kindly provided by Ross Reichard in the Department of Pathology (Neuropathology) at the University of New Mexico, NM, USA.

arteries.52 When rats with bilateral carotid artery occlusion survive longer than 3 days, hypoxic hypoperfusion leads to astrocytosis, microglia activation, loss of oligodendrocytes, and demyelination. Rats with bilateral carotid artery occlusion have high expression of MMP2 in endothelial cells and microglia in white matter.53 In a recent study, treatment with a selective MMP2 inhibitor, AG-3340, reduced blood­brain barrier injury to the white matter and resulted in less myelin damage, suggesting that disruption of the blood­brain barrier by MMP2 was upstream of the myelin damage.44 Consistent results were found with Mmp2 knockout mice.44 In brain tissue from patients with vascular cognitive impairment, inflammatory cells accumulate around hypertensive, fibrotic blood vessels.47,54 Gliotic regions have reactive astrocytes that overexpress MMP2 (figure 4), and macrophages around damaged blood vessels are immunopositive for MMP3 (figure 4).47 Therefore, MMPs might damage blood vessels, disrupting the blood­brain barrier, thus activating microglia and recruiting macrophages that will contribute to the tissue injury as they try to repair the extracellular matrix. Demyelination of ischaemic white matter might occur in both animals and human beings through an MMP-mediated mechanism, including MMP2, MMP3, and possibly MMP9.44,47,53 Other factors might be involved in the progressive inflammation of the white matter in vascular cognitive impairment. MMP2 is an activator of endothelin 1, which is a strong vasoconstrictor that would further compromise blood flow to the deep white matter.55,56 Pathological studies in patients with vascular cognitive impairment detect increased endothelin 1 in the white matter57 and increases in HIF1 that correlated with white matter damage.43 Figure 5 shows a theoretical mechanism linking vascular changes to hypoxia through the central action of HIF1. The dual function of HIF1 in injury and repair suggests that, after the initial injury phase with induction of inflammatory molecules, recovery begins with the activation of molecules that will stimulate regrowth of cells and blood vessels. Chronic intermittent hypoxia results in recurrent apnoeas with periodic decreases in arterial blood oxygen, which predispose patients to cardiorespiratory morbidities. Patients with sleep apnoea can have white matter damage, like that seen on MRI in vascular cognitive impairment.58 In rodents and cell cultures, intermittent hypoxia activates various transcription factors, including HIF1, c-fos, nuclear factor of activated T cells, and NF-B. Intermittent hypoxia is more potent than chronic hypoxia in activating HIF1 and c-fos and results in prolonged accumulation of their mRNAs.59

MMPs and ADAMs in Alzheimer's disease

Neuropathological features of Alzheimer's disease include neuronal tangles and amyloid plaques.60 Deposition of improperly processed amyloid is thought to be a main factor in the pathophysiology of Alzheimer's disease.

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Amyloid precursor protein comprises a transmembrane and an extracellular component. Secretases degrade amyloid precursor protein and the sites of cleavage determine the fate of these protein fragments. The physiological pathway results in the cleavage of the amyloid precursor by -secretase, which produces a soluble component that can be broken down for clearance. ADAM10 and ADAM17 are possible candidates for -secretase.13 Two other secretases (-secretase and -secretase) act together to produce A peptides, A1-40 and A1-42; cleavage of amyloid precursor protein by -secretase produces a fragment of amyloid precursor protein that can be further processed to A1-42 by -secretase. Either type of A can aggregate to form dimers, oligomers, and subsequently fibrils that are deposited in neuropils and in cells.60 When A1-42 builds up in the interstitial fluid from failure of enzymatic breakdown of the molecule, the insoluble fibrils turn into neuritic plaques. MMPs participate in the formation and clearance of the amyloid- peptides (A) in Alzheimer's disease.61,62 MMPs are induced endogenously by the amyloid molecules in blood vessels, astrocytes, and microglia.63 Astrocytes exposed to A1-40 secrete MMP2, MMP3, and MMP9.64 When A is deposited in tissues around the plaques, there is activation of microglia and astrocytosis. This inflammatory response might contribute to neuronal death.65 The increase in expression of MMPs in brain tissue and blood of patients with Alzheimer's disease is probably part of the inflammatory response. An early PCR and immunohistochemistry study showed that MMP9 was expressed in hippocampal neurons in patients with Alzheimer's disease.66 MMP9 degraded amyloid peptides and a latent form of MMP9 was found in brain tissue from the patients. The study authors speculated that the absence of an activated form of MMP9 might have disrupted degradation of amyloid and contributed to the accumulation of insoluble A peptides in plaques. In another study, immunohistochemistry detected MMP3 expression in hippocampal neurons, around amyloid plaques in the cortex, and in the interstitium of white matter.67 Plasma concentrations of MMP9 are increased in Alzheimer's disease;68 however, there is no increase in MMP9 concentrations in the cerebrospinal fluid in Alzheimer's disease.50 This discrepancy remains to be resolved. Deposition of amyloid in brain or in blood vessels in sporadic Alzheimer's disease could be due to overproduction of amyloid, as occurs in familial forms of Alzheimer's disease, or a disruption of clearance. MMP9 can catabolise A.61 Transgenic mice carrying genes from familial forms of Alzheimer's disease, namely the APP and presenilin 1 (PSEN1) genes have increased MMP2 and MMP9 concentrations in astrocytes around amyloid plaques compared with areas without amyloid deposition.61 Microdialysis indicated that Mmp2 and Mmp9 knockout mice had higher levels of A than wild-type mice and treatment with the MMP inhibitor GM-6001 increased A in transgenic mice overexpressing the Swedish variant of

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Hypertension or diabetes hypoperfusion Blood vessel injury (fibrosis or hyalinosis) Injury Hypoxia or ischaemia Activation of FURIN Expression of VEGF and TGF Angiopoietin 2 Repair

Furin

HIF1

pro-MMP14

MMP14

MMP2 and MMP9

pro-MMP2

Angiogenesis and neurogenesis

MMP2

BBB breakdown ? Oedema

Demyelination

Endothelin 1

White matter damage

Vasoconstriction

Aggravates hypoxia

Figure 5: Possible mechanism for white matter injury in vascular cognitive impairment Hypertension, diabetes mellitus, and other diseases that damage blood vessels can initiate white matter injury by increasing risk of thrombosis and small strokes. If the blood flow to the watershed areas of the white matter is compromised by hypotension or by narrowing of the arteries, then hypoxia­ischaemia results, which induces inflammation. Hypoxia secondary to hypoperfusion increases HIF1 concentration, which turns on cassettes of genes associated with injury such as FURIN, and increases expression of VEGF and TGF, which are important in repair. Furin leads to activation of MMP2 through activation of MT-MMP. MMP2 can disrupt the tight junction proteins and open the BBB, leading to oedema. Oedema might also cause demyelination. Additionally, MMP2 might attack myelin and can activate endothelin 1, which causes vasoconstriction through calcium metabolism in the small muscle. Vasoconstriction aggravates the hypoxic state. Conversely, on the repair side, VEGF and TGF activate angiopoietin 2, which acts through the secretion of MMPs to initiate angiogenesis and neurogenesis. BBB=blood­brain barrier. HIF1=hypoxia-inducing factor 1 . MMP=matrix metalloproteinase. MT=membrane type. TGF=transforming growth factor . VEGF=vascular endothelial growth factor.

APP (mutations at positions 670 and 671).61 MMP9 is also able to degrade the fibrillary form of A.63 These findings suggest that MMP9 can contribute to the clearance of soluble and fibrillar A. In familial forms of Alzheimer's disease, the excessive production of amyloid might be sufficient to create the amyloid deposits; however, in the more common sporadic forms, the ability to remove the amyloid that is normally produced might lead to high concentrations of amyloid in the brain (figure 6). In both of these processes, MMPs and ADAMs could have key roles. The therapeutic strategies for Alzheimer's disease include inhibition of the enzymes implicated in amyloid peptide processing. Inhibitors of secretases offer potential to reduce the production of A peptides. Deposition of amyloid peptides in tissues results in an inflammatory response that could be lessened with anti-inflammatory drugs; however, non-steroidal anti-inflammatory drugs and free-radical scavengers have not proved useful. Because ADAM10 and other secretases contribute to

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-secretase site of cleavage

-secretase site of cleavage

APP

-secretase site of cleavage

A

APPs

those without that genotype to prevent disease progression.71 Homozygosity for the 6A allele has been associated with carotid artery stenosis; however, these results were obtained from only 91 patients and will need confirmation.72 In one study, patients who were APOE 4 non-carriers and 6A/6A homozygous were at an increased risk of dementia.73 However, studies of MMP3 polymorphisms in the large Rotterdam cohort did not support a role for variations in MMP3 as a causal factor in dementia.74 These studies focused on dementia as a homogeneous disorder rather than separating patients into Alzheimer's disease and vascular cognitive impairment. The identification of genetic risk factors, such as MMP3 alleles, in vascular cognitive impairment is an important goal that is currently limited by the heterogeneity of this disorder.

A1­42

A1­40 MMP2 and MMP9

MMPs in Parkinson's disease

Parkinson's disease results from neurodegeneration of dopaminergic neurons in the substantia nigra, which is associated with activation of microglia. Recent studies have implicated MMPs in the death of dopaminergic neurons in this disease. In vitro, apoptotic dopaminergic neurons release MMP3, which acts as a microgliaactivating molecule, suggesting that, in addition to degradation of extracellular macromolecules, MMP3 is a signalling molecule, mediating the interaction between apoptotic neurons and microglia.7 TNF released from microglia leads to neuronal death; primary mouse mesencephalic cells in culture die when treated with BH4 (tetrahydrobiopterin), a selective dopaminergic neuronal toxin; however, treatment with the MMP3 inhibitor NNGH (N-isobutyl-N-[4-methoxyphenylsulfonyl]-glycylhydroxamic acid) prolongs cell survival by decreasing TNF release from activated microglia. TNF directly induces neuronal death, suggesting that MMP3-activated microglia might cause neuronal degeneration by releasing proinflammatory cytokines. In addition to the extracellularly triggered mechanisms of apoptosis, MMP3 acts intracellularly in the apoptotic signalling in dopaminergic cells in culture; this action of active MMP3 is linked to caspase 3.75 The mechanisms of this intracellular action of MMP3 are unclear.

A fibrils

Activated microglia

Amyloid break-up products

Amyloid plaques Clearance into the blood

Figure 6: Effects of MMPs and ADAMs in the processing of APP When -secretase cleaves the APP molecule, a soluble fragment of the APP is produced (APPs), which can be further metabolised by proteases and cleared from the brain across the blood­brain barrier. However, if -secretase initiates the cleavage of APP to form an interim product that -secretase cleaves, then the A molecule is formed. The most common form of A is A1-40, which is degraded by MMPs and cleared through the blood­brain barrier: a smaller amount of A1-42 is formed, but this can clump into fibrils that accumulate in amyloid plaques. MMP2 and MMP9 degrade A and aid in its clearance from brain across the blood­brain barrier. Furthermore, microglia are activated by A, adding to the amount of MMP9 available. A=amyloid- peptide. ADAM=a disintegrin and metalloproteinase. APP=amyloid precursor protein. MMP=matrix metalloproteinase. APPs=soluble -amyloid precursor protein.

production of amyloid peptides, and because MMP9 facilitates clearance of A, drugs that inhibit both MMPs and ADAMs might have unexpected effects that need to be identified to determine the therapeutic potential of MMP inhibitors.

MMP3 polymorphisms and dementia

Genetic studies have linked polymorphisms of MMP3 to rheumatoid arthritis and cardiovascular disease, suggesting a role of these MMPs in chronic neuroinflammation.69 Homozygosity for the MMP3 6A allele was associated with worse outcome in a large cohort of patients with rheumatoid arthritis.70 In a study of lipidlowering drugs in coronary artery disease, a beneficial effect on disease progression was associated with the 5A allele, whereas patients with coronary artery disease who were homozygous for the 6A allele (25­30% of the population) were at risk of rapid disease progression and might require more intense lipid-lowering therapy than

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MMPs in CNS repair

Shortly after ischaemic insult, a cascade of events is initiated that begins to repair damage. The factors involved in the repair process might be similar to those found in the healing of an epithelial wound. As in acute injury, HIF1 plays an important part by inducing genes that begin the process of growing new vessels and stimulating neurogenesis. HIF1 activates genes that are implicated in metabolism of glucose, production of red blood cells, and recruitment of cells involved in repair.42 HIF1 induces FURIN, which has a hypoxia-responsive element in the promoter region, as do many genes important in acute injury and repair.76 Furin is an

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intracellular convertase that activates several enzymes, including MMP14. While growing, blood vessels are dependent on the plasminogen-activator system and MMPs. Urokinase plasminogen activator, MMP2, MMP3, and MMP9 have roles in angiogenesis.77 Mechanisms of blood-vessel growth after injury have similarities to abnormal angiogenesis in brain tumours. Gliomas grow rapidly, creating a hypoxic environment with increased HIF1 concentrations; angiogenesis compensates for the absence of oxygen. Malignant glioma cell lines have increased MMP2 concentrations and low TIMP2 concentrations. The targeting of HIF1 with small interfering RNA in glioma cells decreased the expression of MMP2 and raised TIMP2 concentrations.78 Glioma cells have a high level of the angiogenic regulator angiopoietin 2, which is associated with high MMP2 concentrations, suggesting that angiopoietin 2 might promote tumour cell infiltration through activation of MMP2.79 Angiogenesis is important in arteriovenous malformations. Biochemical measurements of MMPs in human brain tissue removed from arteriovenous malformations at surgery showed increased MMP9.80 Concomitant intracerebral injection of adenoviral vectors expressing VEGF and angiopoietin 2 in rats increased angiogenesis; the combination of these molecules increased angiogenesis and production of MMP9 more than VEGF alone.81 When viral vectors that deliver VEGF stimulate the growth of blood vessels, treatment with the tetracycline derivative doxycycline, an inhibitor of MMP, reduces the growth of blood vessels.82 Furthermore, angiogenesis plays an important part in recovery from stroke.83,84 In cancer, inhibition of angiogenesis is a therapeutic goal to reduce tumour growth, whereas angiogenesis is thought to be necessary after stroke. This presents a dilemma in the use of MMP inhibitors in the treatment of vascular disease. Blocking the adverse actions of the MMPs early in the course of the neuroinflammatory response might be beneficial. However, once angiogenesis begins, which seems to be within days of the initial insult in stroke, MMP inhibitors can hinder recovery.85 The migration of neural progenitor cells and the growth of vessels after stroke is dependent on multiple factors, including the stimulation of blood-vessel growth by HIF1 in the presence of decreased oxygen tension in the tissues. Endothelial cells, activated by HIF1induced erythropoietin, secrete MMP2 and MMP9, leading to the movement of neural progenitor cells to the injury site.86 Cells in the subventricular zone are the source of neuroblasts that migrate to the site of injury after a stroke; these cells secrete MMP9 to facilitate movement, which would be blocked with MMP inhibitors.87

Therapeutic strategies

MMP inhibitors have had beneficial effects in animal studies of multiple sclerosis, Guillain-Barré syndrome, meningitis, vascular dementia, and stroke. Acute cerebral

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ischaemia has been most intensively studied. Antibodies to MMPs and broad-spectrum MMP inhibitors, such as BB-94, BB-1101, and GM-6001, reduce blood­brain barrier damage, infarct size, and cell death.88­90 MMP inhibitors protect the brain from haemorrhagic complications of alteplase by reducing the permeability of the blood­brain barrier and preventing alteplase from entering the brain and activating MMPs.91,92 Treatment with MMP inhibitors in stroke needs to be given early in the first few days after the injury to prevent blocking the recovery phase. MRI has shown in rats that, although the broad-spectrum inhibitor BB-1101 blocked the early opening of the blood­brain barrier at 3 h after a 90-min middle cerebral artery occlusion with reperfusion, the inhibitor had no effect on lesion size at 48 h, and recovery over 3 weeks was slowed.85 Autoimmune and infectious diseases have been successfully treated with MMP inhibitors in animals. Damage to the blood­brain barrier seen in experimentally induced meningitis and experimental allergic encephalomyelitis can be reduced with MMP inhibitors. MMPs are important in the pathogenesis of bacterial meningitis and are thought to contribute to the damage seen in children with meningitis despite use of appropriate antibiotics. A water-soluble inhibitor of MMPs and TACE, TNF-484, is effective in animals.93 Doxycycline blocks secondary damage in experimental bacterial meningitis in rodents.94 Tetracycline derivates, such as doxycycline and minocycline, inhibit inflammation and reduce MMP concentrations. Minocycline given to patients with multiple sclerosis reduces the number of gadolinium-enhancing lesions on MRI.95 Doxycycline has been used in treatment of MMP-mediated vascular diseases and reduced vascular damage in an animal model of Marfan's syndrome with improvement in aortic aneurysms after 1-year treatment. 96 Tetracyclines can be given in low doses for several years without adverse effects and, when given in combination with interferon beta, were effective in controlling inflammation in mice with experimental allergic encephalomyelitis.97 The function of MMPs in the progressive damage to the white matter in vascular cognitive impairment might offer opportunities for treatment because of the possible contribution of MMPs to the damage. A caveat is that MMP9 might be important in remyelination, as oligodendrocyte regrowth is facilitated by MMP9.98 Although there are MMP inhibitors that are selective for MMP2 and MMP9,99 most available MMP inhibitors are broad-spectrum drugs.100 For the short-term treatment strategies envisioned for acute neurological diseases, such as early opening of the blood­brain barrier in ischaemia and infection, a broad-spectrum inhibitor might be useful. The problem with broad-spectrum inhibitors is that they might block important functions, such as remodelling of the extracellular matrix. In trials of MMP inhibitors in cancer, joint stiffness was the side-effect that limited treatment.101 Another challenge in the development of MMP inhibitors as acute treatments is their poor solubility;

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studies are needed to facilitate improvement of delivery systems. For long-term use, selective MMP inhibitors might be needed to avoid prolonged broad-spectrum effects. Metabolism and efficacy of MMP inhibitors vary in different species. For example, drugs that effectively close the blood­brain barrier in rats after lipopolysaccharide challenge are ineffective in mice.102 In vascular cognitive impairment, decreasing white matter damage caused by ischaemic injury and hypoxic hypoperfusion is a likely therapeutic aim. Many patients with diabetes mellitus have white matter lesions, which are thought to be associated with subtle disruption of the blood­brain barrier.103 If so, treatment with a drug that blocks MMPs, such as minocycline, might be useful. Similarly, damage to the white matter caused by hypertension might respond to drugs that reduce the expression or activation of MMPs. Because vascular cognitive impairment is a heterogeneous disease, identification of a subgroup of patients with a progressive inflammatory component in the pathophysiology will be necessary. However, the consequences of long-term treatment with MMP inhibitors would have to be monitored carefully for side-effects. Even more speculative is the possible use of MMP inhibitors in the treatment of Alzheimer's disease. The role of MMPs and ADAMs in Alzheimer's disease is complex because of their dual function in the breakdown of amyloid to form A and in the clearance of A from the brain. Theoretically, treatment with MMP inhibitors could impede amyloid clearance because MMP9 seems to facilitate the removal of the amyloid peptides. Use of MMP inhibitors in Parkinson's disease might show great promise as the death of dopaminergic neurons seems to be associated with release of MMPs by the activated cells around them. Much more information is needed before MMP inhibitors can be tested for use as treatment in these chronic disorders.

Search strategy and selection criteria References for this Review were identified through searches of PubMed with the search terms "brain and MMPs", "Alzheimer's disease and MMPs", and "Parkinson's disease and MMPs", from January 1990 to July 2008. The final reference list was generated on the basis of relevance to the topics covered in this Review. Abstracts were excluded.

Acknowledgments The studies from the author's laboratory were supported by grants from the National Institute of Neurological Diseases and Stroke (RO1 NS045847 and RO1 NS052305). Conflicts of interest I have no conflicts of interest. References 1 Cauwe B, Van den Steen PE, Opdenakker G. The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinases. Crit Rev Biochem Mol Biol 2007; 42: 113­85. 2 Cunningham LA, Wetzel M, Rosenberg GA. Multiple roles for MMPs and TIMPs in cerebral ischemia. Glia 2005; 50: 329­39. 3 Leppert D, Lindberg RL, Kappos L, Leib SL. Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis. Brain Res Brain Res Rev 2001; 36: 249­57. 4 Yong VW. Metalloproteinases: mediators of pathology and regeneration in the CNS. Nat Rev Neurosci 2005; 6: 931­44. 5 Overall CM, Lopez-Otin C. Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat Rev Cancer 2002; 2: 657­72. 6 Van Wart HE, Birkedal Hansen H. The cysteine switch: a principle of regulation of metalloproteinase activity with potential applicability to the entire matrix metalloproteinase gene family. Proc Natl Acad Sci USA 1990; 87: 5578­82. 7 Kim YS, Kim SS, Cho JJ, et al. Matrix metalloproteinase-3: a novel signaling proteinase from apoptotic neuronal cells that activates microglia. J Neurosci 2005; 25: 3701­11. 8 Strongin AY, Collier I, Bannikov G, Marmer BL, Grant GA, Goldberg GI. Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J Biol Chem 1995; 270: 5331­38. 9 Nagase H. Activation mechanisms of matrix metalloproteinases. Biol Chem 1997; 378: 151­60. 10 Gu Z, Kaul M, Yan B, et al. S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 2002; 297: 1186­90. 11 Blobel CP. Remarkable roles of proteolysis on and beyond the cell surface. Curr Opin Cell Biol 2000; 12: 606­12. 12 Baker AH, Edwards DR, Murphy G. Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci 2002; 115: 3719­27. 13 Buxbaum JD, Liu KN, Luo Y, et al. Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alphasecretase cleavage of the Alzheimer amyloid protein precursor. J Biol Chem 1998; 273: 27765­67. 14 Gearing AJ, Beckett P, Christodoulou M, et al. Processing of tumour necrosis factor-alpha precursor by metalloproteinases. Nature 1994; 370: 555­57. 15 Brew K, Dinakarpandian D, Nagase H. Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta 2000; 1477: 267­83. 16 Leco KJ, Khokha R, Pavloff N, Hawkes SP, Edwards DR. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrix-associated protein with a distinctive pattern of expression in mouse cells and tissues. J Biol Chem 1994; 269: 9352­60. 17 Wallace JA, Alexander S, Estrada EY, Hines C, Cunningham LA, Rosenberg GA. Tissue inhibitor of metalloproteinase-3 is associated with neuronal death in reperfusion injury. J Cereb Blood Flow Metab 2002; 22: 1303­10.

Conclusions

Much information has accumulated on the role of MMPs in acute disorders such as stroke, multiple sclerosis, and meningitis. These enzymes participate in the final common pathway after pathological changes to blood vessels and extracellular matrix around cells, which leads to cell death and increased permeability of the blood­brain barrier. Chronic neurological diseases of the elderly, namely, vascular cognitive impairment, Alzheimer's disease, and Parkinson's disease, are also affected by MMPs and ADAMs. However, in addition to the function of MMPs and ADAMs in disease states, these enzymes have many roles in physiological processes, such as angiogenesis and neurogenesis. This dual action of metalloproteinases complicates efforts at treatment with broad-spectrum MMP inhibitors. More research is needed to understand the diverse roles of these proteases to design specific drugs and devise therapeutic strategies.

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