Partial reduction of BACE1 improves synaptic plasticity, recent and remote memories in Alzheimer’s disease transgenic mice

Abstract

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.

7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, Reverses Memory Deficits and BACE1 Elevation in a Mouse Model of Alzheimer's Disease

“…It is also well documented that genetic reductions of BDNF or TrkB deteriorate basal synaptic transmission and/ or LTP at the hippocampal Schaffer collateral-CA1 pathway and cause memory deficits in mice (Korte et al, 1995;Linnarsson et al, 1997;Minichiello, 2009;Minichiello et al, 1999;Pang and Lu, 2004;Patterson et al, 1996). Consistent with these results, we recently reported that partial reductions of Ab induced by heterozygous BACE1 gene deletion (BACE1 + /-) rescue synaptic and mnemonic dysfunctions in 5XFAD mice with the restoration of reduced hippocampal BDNF and TrkB phosphorylation to normal levels (Kimura et al, 2010). Taken collectively, our results indicate that BDNF-TrkB dysfunction is a crucial mechanism downstream to Ab accumulation in 5XFAD mice, and that reversal of the deficient BDNF-TrkB signaling with 7,8-DHF may be sufficient to directly ameliorate memory impairments associated with AD.…”

“…Spontaneous alternation performance was tested using a symmetrical Y-maze, as described previously (Kimura et al, 2010;Ohno et al, 2004). Each mouse was placed in the center of the Y-maze and was allowed to explore freely through the maze during an 8-min session.…”

“…Sandwich Ab ELISAs were performed as described previously (Devi and Ohno, 2010a; Devi and Ohno, 2010b; Kimura et al, 2010). Briefly, each hemibrain sample was extracted in 8X cold 5 M guanidine HCl plus 50 mM Tris HCl (pH 8.0) buffer, and centrifuged at 20 000 g for 1 h at 41C to remove insoluble material.…”

Trimethylamine‐N‐oxide promotes brain aging and cognitive impairment in mice

“…We tested the effects of TMAO on spatial working memory in mice with the Y‐maze (Kimura, Devi & Ohno, 2010; Ohno et al., 2004) (Figure 2a–d). There was no significant difference among the four groups in the total number of arms entered, which indicated the mice in the four groups had similar working memories (Figure 2a).…”

Effect of the beta secretase-1 inhibitor on the amyloid C-terminal fragment of amyloid precursor protein processing in a hyperphosphorylated tau rat model

“…We also found that BACE1 inhibitor ameliorated the memory defects resulting from changes in the quantity and distribution of neurotoxic βCTF (Kimura et al, 2010). In-depth understanding of the involvement of βCTF in neurodegeneration is an important determinant for the use of BACE1 inhibitor and γ-secretase inhibition as major therapeutic strategies for AD; however, there is controversy about which one would be more appropriate (Golde and Younkin, 2001).…”