Abnormal Expression and Distribution of MMP2 at Initial Stages of Alzheimer's Disease-Related Pathology

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Metalloproteinases (MMPs) are implicated in amyloid-beta (Aβ) clearance in Alzheimer's disease (AD).
• Specific MMPs like MMP2, MMP3, MMP9, and MT1-MMP have demonstrated roles in degrading soluble and fibrillar Aβ.

Purpose of the Study:

• To investigate the role and expression of MMP2 in early-stage Alzheimer's disease pathology.
• To determine if MMP2 interacts with tau protein in the context of neurofibrillary tangle formation.

Main Methods:

• Western blotting and gelatin zymography to assess active MMP2 levels in human brain tissue.
• Confocal microscopy to visualize the co-localization of MMP2 with phospho-tau in neurofibrillary tangles.
• In vitro assays using recombinant and fractionated tau proteins to test MMP2's proteolytic activity.

Main Results:

• Increased expression of active MMP2 was observed in the entorhinal cortex during early stages of AD (Braak stages I/II-0 and III/IV-A).
• MMP2 co-localized with phospho-tau within neurofibrillary tangles and dystrophic neurites.
• MMP2 effectively cleaved recombinant tau in vitro but showed no cleavage activity against hyperphosphorylated or dephosphorylated tau from paired helical filament fractions.

Conclusions:

• The accumulation of MMP2 in neurofibrillary tangles suggests a localized response within AD brains.
• The loss of MMP2's proteolytic activity on pathological tau forms indicates a potential mechanism to prevent the generation of toxic truncated tau species.
• These findings highlight a complex role for MMP2 in AD pathogenesis, possibly involving both Aβ clearance and tau proteolysis modulation.