The MMP-2/TIMP-2 System in Alzheimer Disease

Alzheimer Disease (AD) is the most prevalent type of dementia. Pathological changes in the AD brain include Amyloid β-protein (Aβ) plaques and Neurofibrillary Tangles (NFTs), as well as extensive neuronal and synaptic loss. Matrix Metalloproteinase-2 (MMP-2) is a neutral, zinc-dependent protease that primarily targets extracellular matrix proteins. MMP-2 activity is strictly controlled, and its dysregulation has been implicated in a variety of pathologies, including AD. In this brief review, we discussed the contributions of dysregulated MMP-2 activity and an imbalanced interaction between MMP-2 and its endogenous inhibitor, Tissue Inhibitors of Metalloproteinase-2 (TIMP-2), to AD. We also described the underlying mechanisms of the effects of MMP-2/TIMP-2, both beneficial and detrimental, on AD, including: (1) MMP-2 directly degrades Aβ resulting in the clearance of Aβ deposits. Conversely, Aβ-induced MMP-2 may contribute to brain parenchymal destruction. (2) MMP-2 induces breakdown of BBB, and this deleterious effect could be reversed by TIMP-2. (3) MMP-2 disrupts oxidative homeostasis in AD. (4) MMP-2 has both proinflammatory/pro-angiogenetic and antiinflammatory/ anti-angiogenetic effects on AD. Besides, we discuss the clinical utility of MMP- 2/TIMP-2 as therapeutic targets for AD.

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Isolation and Characterization of Patient-derived, Toxic, High Mass Amyloid β-Protein (Aβ) Assembly from Alzheimer Disease Brains

Journal of Biological Chemistry ◽

10.1074/jbc.m109.000208 ◽

2009 ◽

Vol 284 (47) ◽

pp. 32895-32905 ◽

Cited By ~ 120

Author(s):

Akihiko Noguchi ◽

Satoko Matsumura ◽

Mari Dezawa ◽

Mari Tada ◽

Masako Yanazawa ◽

...

Keyword(s):

Alzheimer Disease ◽

Amyloid Β ◽

High Mass ◽

Amyloid Β Protein ◽

Isolation And Characterization ◽

Β Protein

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The Tottori (D7N) and English (H6R) Familial Alzheimer Disease Mutations Accelerate Aβ Fibril Formation without Increasing Protofibril Formation

Journal of Biological Chemistry ◽

10.1074/jbc.m608220200 ◽

2006 ◽

Vol 282 (7) ◽

pp. 4916-4923 ◽

Cited By ~ 77

Author(s):

Yukiko Hori ◽

Tadafumi Hashimoto ◽

Yosuke Wakutani ◽

Katsuya Urakami ◽

Kenji Nakashima ◽

...

Keyword(s):

Alzheimer Disease ◽

Amyloid Fibril ◽

Amyloid Β ◽

Fibril Formation ◽

Amyloid Β Protein ◽

Protein Precursor ◽

Amyloid Fibril Formation ◽

Β Protein ◽

Familial Alzheimer Disease ◽

Aβ Production

A subset of Alzheimer disease cases is caused by autosomal dominant mutations in genes encoding the amyloid β-protein precursor or presenilins. Whereas some amyloid β-protein precursor mutations alter its metabolism through effects on Aβ production, the pathogenic effects of those that alter amino acid residues within the Aβ sequence are not fully understood. Here we examined the biophysical effects of two recently described intra-Aβ mutations linked to early-onset familial Alzheimer disease, the D7N Tottori-Japanese and H6R English mutations. Although these mutations do not affect Aβ production, synthetic Aβ(1-42) peptides carrying D7N or H6R substitutions show enhanced fibril formation. In vitro analysis using Aβ(1-40)-based mutant peptides reveal that D7N or H6R mutations do not accelerate the nucleation phase but selectively promote the elongation phase of amyloid fibril formation. Notably, the levels of protofibrils generated from D7N or H6R Aβ were markedly inhibited despite enhanced fibril formation. These N-terminal Aβ mutations may accelerate amyloid fibril formation by a unique mechanism causing structural changes of Aβ peptides, specifically promoting the elongation process of amyloid fibrils without increasing metastable intermediates.

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