BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease.
beta-site APP cleaving enzyme 1 (BACE1) is the beta-secretase enzyme required for generating pathogenic beta-amyloid (Abeta) peptides in Alzheimer's disease (AD). BACE1 knockout mice lack Abeta and are phenotypically normal, suggesting that therapeutic inhibition of BACE1 may be free of mechanism-based side effects. However, direct evidence that BACE1 inhibition would improve cognition is lacking. Here we show that BACE1 null mice engineered to overexpress human APP (BACE1(-/-).Tg2576(+)) are rescued from Abeta-dependent hippocampal memory deficits. Moreover, impaired hippocampal cholinergic regulation of neuronal excitability found in the Tg2576 AD model is ameliorated in BACE1(-/-).Tg2576(+) bigenic mice. The behavioral and electrophysiological rescue of deficits in BACE1(-/-).Tg2576(+) mice is correlated with a dramatic reduction of cerebral Abeta40 and Abeta42 levels and occurs before amyloid deposition in Tg2576 mice. Our gene-based approach demonstrates that lower Abeta levels are beneficial for AD-associated memory impairments, validating BACE1 as a therapeutic target for AD.
Ohno
Masuo
M
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. ohno@northwestern.edu
Sametsky
Evgeny A
EA
Younkin
Linda H
LH
Oakley
Holly
H
Younkin
Steven G
SG
Citron
Martin
M
Vassar
Robert
R
Disterhoft
John F
JF
D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology* / Q000523:psychology*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000172:deficiency*; D001921:Brain / Q000378:metabolism; D002799:Cholinergic Fibers; D010450:Endopeptidases; D006624:Hippocampus / Q000503:physiopathology*; D006801:Humans; D008569:Memory Disorders / Q000209:etiology / Q000523:psychology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse