Partial reduction of BACE1 improves synaptic plasticity, recent and remote memories in Alzheimer's disease transgenic mice.
beta-Site amyloid precursor protein cleaving enzyme 1 (BACE1) initiates amyloid-beta (Abeta) generation that is central to the pathophysiology of Alzheimer's disease (AD). Therefore, lowering Abeta levels by BACE1 manipulations represents a key therapeutic strategy, but it remains unclear whether partial inhibition of BACE1, as expected for AD treatments, can improve memory deficits. In this study, we used heterozygous BACE1 gene knockout (BACE1+/-) mice to evaluate the effects of partial BACE1 suppression on different types of synaptic and cognitive dysfunctions in Alzheimer's transgenic mice (5XFAD model). We found that approximately 50% BACE1 reductions rescued deficits of 5XFAD mice not only in hippocampus-dependent memories as tested by contextual fear conditioning and spontaneous alternation Y-maze paradigms but also in cortex-dependent remote memory stabilization during 30 days after contextual conditioning. Furthermore, 5XFAD-associated impairments in long-term potentiation (a synaptic model of learning and memory) and declines in synaptic plasticity/learning-related brain-derived neurotrophic factor-tyrosine kinase B signaling pathways were prevented in BACE1+/-.5XFAD mice. Finally, these improvements were related with reduced levels of beta-secretase-cleaved C-terminal fragment (C99), Abeta peptides and plaque burden in relevant brain regions of BACE1+/-.5XFAD mice. Therefore, our findings provide compelling evidence for beneficial effects of partially BACE1-inhibiting approaches on multiple forms of functional defects associated with AD.
Kimura
Ryoichi
R
Center for Dementia Research, Nathan Kline Institute, New York University School of Medicine, Orangeburg, New York 10962, USA.
Devi
Latha
L
Ohno
Masuo
M
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D003214:Conditioning, Classical / Q000502:physiology; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D005239:Fear / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000235:genetics; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics*; D018408:Patch-Clamp Techniques / Q000379:methods; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C543304:amyloid beta-protein precursor C-terminal fragment beta, human; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human