Premium
S3‐03–02: Transgenic mice with the arctic APP mutation as animal models of Alzheimer's disease
Author(s) -
Nilsson Lars
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.386
Subject(s) - genetically modified mouse , senile plaques , pathogenesis , transgene , morris water navigation task , neuropathology , immunostaining , amyloid (mycology) , extracellular , amyloid precursor protein , protein aggregation , zebrafish , disease , pathology , biology , neuroscience , medicine , alzheimer's disease , microbiology and biotechnology , biochemistry , gene , hippocampus , immunohistochemistry
metabolism via treatment with pharmacologic inhibitors of ATP production causes BACE1 levels to increase in the brains of an APP transgenic model of AD, the Tg2576 mouse. The elevated BACE1 levels in turn cause increased APP amyloidogenic processing, A production, and amyloid plaque formation. These results suggest that impaired energy metabolism may play an important role in the early phases of AD pathogenesis. In addition, using a novel mono-specific anti-BACE1 antibody, we have shown that BACE1 levels are increased around the A 42 cores of amyloid plaques in AD and two APP transgenic mouse models: Tg2576 and 5XFAD mice. BACE1 levels are elevated in presynaptic neuronal structures (likely dystrophic neurites) that surround amyloid plaques, and BACE1 co-localizes with APP in these structures. Conclusions: Our results suggest that increased amyloidogenic processing of APP occurs in dystrophic neurites around plaques, thus exacerbating amyloid deposition. Taken together, our work is consistent with the hypothesis that impaired energy metabolism may lead to increased BACE1 levels and subsequent elevation of A generation. Once amyloid plaques form, A neurotoxicity causes BACE1 levels to increase further in dystrophic neurites around plaques, thus accelerating A formation and plaque growth via a positivefeedback loop.