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Partial reduction of BACE1 improves synaptic plasticity, recent and remote memories in Alzheimer’s disease transgenic mice
Author(s) -
Kimura Ryoichi,
Devi Latha,
Ohno Masuo
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2010.06608.x
Subject(s) - synaptic plasticity , neuroscience , long term potentiation , spontaneous alternation , hippocampus , fear conditioning , genetically modified mouse , amyloid precursor protein , amyloid beta , transgene , amyloid precursor protein secretase , morris water navigation task , alzheimer's disease , memory consolidation , psychology , biology , medicine , disease , receptor , amygdala , biochemistry , gene
J. Neurochem. (2010) 10.1111/j.1471‐4159.2010.06608.x Abstract β‐Site amyloid precursor protein cleaving enzyme 1 (BACE1) initiates amyloid‐β (Aβ) generation that is central to the pathophysiology of Alzheimer’s disease (AD). Therefore, lowering Aβ 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 ∼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 β‐secretase‐cleaved C‐terminal fragment (C99), Aβ 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.