Abstract
Alzheimer’s disease (AD) is a chronic neurodegenerative disease leading to dementia, which is characterized by progressive memory loss and other cognitive dysfunctions. Recent studies have attested that noninvasive repetitive transcranial magnetic stimulation (rTMS) may help improve cognitive function in patients with AD. However, the majority of these studies have focused on the effects of high-frequency rTMS on cognitive function, and little is known about low-frequency rTMS in AD treatment. Furthermore, the potential mechanisms of rTMS on the improvement of learning and memory also remain poorly understood. In the present study, we reported that severe deficits in spatial learning and memory were observed in APP23/PS45 double transgenic mice, a well known mouse model of AD. Furthermore, these behavioral changes were accompanied by the impairment of long-term potentiation (LTP) in the CA1 region of hippocampus, a brain region vital to spatial learning and memory. More importantly, 2-week low-frequency rTMS treatment markedly reversed the impairment of spatial learning and memory as well as hippocampal CA1 LTP. In addition, low-frequency rTMS dramatically reduced amyloid-β precursor protein (APP) and its C-terminal fragments (CTFs) including C99 and C89, as well as β-site APP-cleaving enzyme 1 (BACE1) in the hippocampus. These results indicate that low-frequency rTMS noninvasively and effectively ameliorates cognitive and synaptic functions in a mouse model of AD, and the potential mechanisms may be attributed to rTMS-induced reduction in Aβ neuropathology.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder that affects a large number of elderly people and is characterized clinically by progressive loss of memory and decline of multiple cognitive abilities (Nie et al, 2011)
We further explored the influence of repetitive transcranial magnetic stimulation (rTMS) on hippocampal long-term potentiation (LTP) and the pathological changes of AD including neuritic plaques, amyloid-β precursor protein (APP) processing and BACE1 expression
To test the potential rescue effect of rTMS on AD, we first examined the effects of low-frequency rTMS on spatial learning and memory by using a hippocampus-dependent learning and memory task, the Morris water maze, in APP23/PS45 double transgenic AD mice
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder that affects a large number of elderly people and is characterized clinically by progressive loss of memory and decline of multiple cognitive abilities (Nie et al, 2011). Aβ derives from the amyloid-β precursor protein (APP), which is cleaved by β-secretase and γ-secretase to yield Aβ, and β-site APP-cleaving enzyme 1 (BACE1) is the β-secretase in vivo (Sinha et al, 1999; Vassar et al, 1999; Yan et al, 1999; Hussain et al, 2000; Ly et al, 2013). Knockdown or knockout BACE1 expression reduces, even abolishes Aβ generation (Cai et al, 2001; Luo et al, 2001; Roberds et al, 2001; Kao et al, 2004). These observations suggest that an increase in BACE1 expression may contribute to the pathogenesis of AD
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