학술논문
Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer's disease mutations but not by inhibition of BACE1
Document Type
Academic Journal
Author
Source
Molecular Neurodegeneration. September 14, 2020, Vol. 15 Issue 1
Subject
Language
English
ISSN
1750-1326
Abstract
Author(s): Erik C. B. Johnson[sup.1,2], Kaitlyn Ho[sup.1], Gui-Qiu Yu[sup.1], Melanie Das[sup.1], Pascal E. Sanchez[sup.1], Biljana Djukic[sup.1], Isabel Lopez[sup.1], Xinxing Yu[sup.1], Michael Gill[sup.1], Weiping Zhang[sup.3], Jeanne T. Paz[sup.1,2], Jorge J. Palop[sup.1,2] [...]
Background Alzheimer's disease (AD) is the most frequent and costly neurodegenerative disorder. Although diverse lines of evidence suggest that the amyloid precursor protein (APP) is involved in its causation, the precise mechanisms remain unknown and no treatments are available to prevent or halt the disease. A favorite hypothesis has been that APP contributes to AD pathogenesis through the cerebral accumulation of the amyloid-[beta] peptide (A[beta]), which is derived from APP through sequential proteolytic cleavage by BACE1 and [gamma]-secretase. However, inhibitors of these enzymes have failed in clinical trials despite clear evidence for target engagement. Methods To further elucidate the roles of APP and its metabolites in AD pathogenesis, we analyzed transgenic mice overexpressing wildtype human APP (hAPP) or hAPP carrying mutations that cause autosomal dominant familial AD (FAD), as well as App knock-in mice that do not overexpress hAPP but have two mouse App alleles with FAD mutations and a humanized A[beta] sequence. Results Although these lines of mice had marked differences in cortical and hippocampal levels of APP, APP C-terminal fragments, soluble A[beta], A[beta] oligomers and age-dependent amyloid deposition, they all developed cognitive deficits as well as non-convulsive epileptiform 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 (C99), soluble A[beta], A[beta] oligomers, and amyloid deposits in transgenic mice expressing FAD-mutant hAPP, but did not improve their network dysfunction and behavioral abnormalities, even when initiated at early stages before amyloid deposits were detectable. Conclusions hAPP transgenic and App knock-in mice develop similar pathophysiological alterations. APP and its metabolites contribute to AD-related functional alterations through complex combinatorial mechanisms that may be difficult to block with BACE inhibitors and, possibly, also with other anti-A[beta] treatments. Keywords: Alzheimer's disease, Amyloid, APP, APP-KI, App.sup.NL-G-F, BACE, Behavior, Calbindin, C-Fos, Epilepsy, Epileptiform, I5, Inhibitor, J20, Knock-in, Learning and memory, Oligomers, SWD
Background Alzheimer's disease (AD) is the most frequent and costly neurodegenerative disorder. Although diverse lines of evidence suggest that the amyloid precursor protein (APP) is involved in its causation, the precise mechanisms remain unknown and no treatments are available to prevent or halt the disease. A favorite hypothesis has been that APP contributes to AD pathogenesis through the cerebral accumulation of the amyloid-[beta] peptide (A[beta]), which is derived from APP through sequential proteolytic cleavage by BACE1 and [gamma]-secretase. However, inhibitors of these enzymes have failed in clinical trials despite clear evidence for target engagement. Methods To further elucidate the roles of APP and its metabolites in AD pathogenesis, we analyzed transgenic mice overexpressing wildtype human APP (hAPP) or hAPP carrying mutations that cause autosomal dominant familial AD (FAD), as well as App knock-in mice that do not overexpress hAPP but have two mouse App alleles with FAD mutations and a humanized A[beta] sequence. Results Although these lines of mice had marked differences in cortical and hippocampal levels of APP, APP C-terminal fragments, soluble A[beta], A[beta] oligomers and age-dependent amyloid deposition, they all developed cognitive deficits as well as non-convulsive epileptiform 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 (C99), soluble A[beta], A[beta] oligomers, and amyloid deposits in transgenic mice expressing FAD-mutant hAPP, but did not improve their network dysfunction and behavioral abnormalities, even when initiated at early stages before amyloid deposits were detectable. Conclusions hAPP transgenic and App knock-in mice develop similar pathophysiological alterations. APP and its metabolites contribute to AD-related functional alterations through complex combinatorial mechanisms that may be difficult to block with BACE inhibitors and, possibly, also with other anti-A[beta] treatments. Keywords: Alzheimer's disease, Amyloid, APP, APP-KI, App.sup.NL-G-F, BACE, Behavior, Calbindin, C-Fos, Epilepsy, Epileptiform, I5, Inhibitor, J20, Knock-in, Learning and memory, Oligomers, SWD