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Unaltered secretion of beta-amyloid precursor protein in gelatinase A (matrix metalloproteinase 2)-deficient mice
1Institute for Virus Research, Kyoto University, 53 Kawahara, Syogo-in, Sakyo-ku, Kyoto 606-01, Japan.
Abstract:
The beta-amyloid peptide, which forms extracellular cerebral deposits in Alzheimer's disease, is derived from a large membrane-spanning glycoprotein referred to as the beta-amyloid precursor protein (APP). The APP is normally cleaved within the beta-amyloid region by a putative proteinase (alpha-secretase) to generate large soluble amino-terminal derivatives of APP, and this event prevents the beta-amyloid peptide formation. It has been suggested that the gelatinase A (matrix metalloproteinase 2, a 72-kDa type IV collagenase) may act either as alpha-secretase or as beta-secretase. Mice devoid of gelatinase A generated by gene targeting develop normally, except for a subtle delay in their growth, thus providing a useful system to examine the role of gelatinase A in the cleavage and secretion of APP in vivo. We show here that APP is cleaved within the beta-amyloid region and secreted into the extracellular milieu of brain and cultured fibroblasts without gelatinase A activity. The data suggest that gelatinase A does not play an essential role in the generation and release of soluble derivatives of APP at physiological conditions.
Insights
Gelatinase A does not appear essential for processing the beta-amyloid precursor protein (APP). Studies show APP is cleaved and secreted even without gelatinase A, suggesting it has no vital role in Alzheimer's disease pathology.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Beta-amyloid peptide aggregates in Alzheimer's disease (AD).
- Beta-amyloid precursor protein (APP) is the source of beta-amyloid.
- Alpha-secretase cleavage of APP prevents beta-amyloid formation.
Purpose of the Study:
- To investigate the role of gelatinase A (matrix metalloproteinase 2) in APP processing.
- To determine if gelatinase A functions as alpha-secretase or beta-secretase in vivo.
- To assess APP cleavage and secretion in gelatinase A-deficient mice.
Main Methods:
- Gene targeting to create gelatinase A-deficient mice.
- Analysis of APP cleavage and secretion in brain tissue and cultured fibroblasts.
- Comparison of APP processing in wild-type versus knockout mice.
Main Results:
- Mice lacking gelatinase A exhibited normal development with only minor growth delays.
- APP was effectively cleaved within the beta-amyloid region and secreted in knockout mice.
- Absence of gelatinase A did not impede the generation or release of soluble APP derivatives.
Conclusions:
- Gelatinase A is not essential for the physiological cleavage and secretion of APP.
- The enzyme does not play a critical role in the generation of soluble APP fragments.
- Findings suggest gelatinase A is unlikely to be a primary target for modulating APP processing in AD.