Abstract
β - but not γ-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia
Highlights
Amyloid deposition of Ab peptide characterizes AD
APP processing is genetically linked to AD pathogenesis, which is consistent with a common mechanism involving toxic APP metabolites in both dementias and prompts the question whether blocking APP processing ameliorates FDD
Further processing of b-carboxyl terminal fragment (b-CTF) by g-secretase cleavage releases amyloid-b, which is reputed to be central to AD pathophysiology
Summary
Amyloid deposition of Ab peptide characterizes AD. Ab derives from sequential cleavage of APP by b- and g-secretases. Mutations in either APP or the g-secretase genes PSEN1/2 cause familial AD (FAD). Mutation of BRI2/ITM2b causes an AD-like familial dementia (FDD) with amyloid deposits. The FDD plaques contain Ab and ADan, which derives from processing of mutant BRI2 protein by pro-protein convertases. Since amyloidogenic peptides are believed to cause dementias, transgenic mice carrying mutant APP, PSEN1/2 or BRI2/ITM2b are used to model these dementias, as over-expression is necessary to reproduce amyloidosis. Over-expression of mutant genes might produce harmful effects unrelated to dementias and lead to erroneous information concerning pathogenesis and therapy of human diseases. The clinical failures of compounds efficacious in transgenic models support this hypothesis. APP and BRI2 functionally interact, and that APP mediates FDD neuropathology
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