Johnson, Erik C. B., Ho, Kaitlyn, Das, Melanie, Sanchez , Pascal, Djukic, Biljana, Yu, Xinxing, Lopez, Isabel, Gill, Michael, Paz, Jeanne, Palop, Jorge and Mucke, Lennart (2020) Behavioral and neural network abnormalities of human APP transgenic mice resemble those of App knockin mice but are not prevented by early inhibition of BACE1. Molecular neurodegeneration, 15 (1).

Abstract

Alzheimer’s disease (AD) is the most frequent and costly neurodegenerative disorder and has been recalcitrant to therapeutic interventions. Diverse lines of evidence suggest that the amyloid precursor protein (APP) is involved in its causation. However, the precise mechanisms remain unknown. A favorite hypothesis has been that APP contributes to AD pathogenesis through the cerebral accumulation of the amyloid-peptide (A), which is derived from APP through sequential proteolytic cleavage by BACE1 and-secretase. However, inhibitors of these enzymes have failed in clinical trials despite clear evidence for target engagement. To shed light on this puzzling situation, we compared transgenic mice overexpressing wildtype human APP (hAPP) or hAPP carrying mutations that cause autosomal dominant familial AD (FAD) with knockin mice that do not overexpress hAPP but have two mouse App alleles with FAD mutations and a humanized A sequence. Although these lines of mice had marked differences in cortical and hippocampal levels of APP, APP C-terminal fragments, soluble A, A oligomers, and age- dependent amyloid deposition, they all developed cognitive deficits as well as non-convulsive epileptic activity, a type of network dysfunction that also occurs in a substantive proportion of humans with AD. Pharmacological inhibition of BACE1 effectively reduced levels of amyloidogenic APP C-terminal fragments, soluble A, A oligomers, and amyloid deposits in transgenic mice expressing FAD-mutant hAPP, but did not improve any of their functional deficits, even when initiated at early stages before amyloid deposits were detectable. We conclude that APP contributes to AD-related functional alterations through one or more complex mechanisms that may be impossible to block with treatments selectively aimed at A or other secretase- generated APP metabolites.

Item Type:	Article
Date Deposited:	26 Sep 2020 00:45
Last Modified:	26 Sep 2020 00:45
URI:	https://oak.novartis.com/id/eprint/39442