Regulation of Synaptic Amyloid-β Generation through BACE1 Retrograde Transport in a Mouse Model of Alzheimer's Disease

Abstract

Amyloid-␤ (A␤) peptides play a key role in synaptic damage and memory deficits in the early pathogenesis of Alzheimer's disease (AD).Abnormal accumulation of A␤ at nerve terminals leads to synaptic pathology and ultimately to neurodegeneration. ␤-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the major neuronal ␤-secretase for A␤ generation. However, the mechanisms regulating BACE1 distribution in axons and ␤ cleavage of APP at synapses remain largely unknown. Here, we reveal that dynein-Snapin-mediated retrograde transport regulates BACE1 trafficking in axons and APP processing at presynaptic terminals. BACE1 is predominantly accumulated within late endosomes at the synapses of AD-related mutant human APP (hAPP) transgenic (Tg) mice and patient brains. Defective retrograde transport by genetic ablation of snapin in mice recapitulates late endocytic retention of BACE1 and increased APP processing at presynaptic sites. Conversely, overexpressing Snapin facilitates BACE1 trafficking and reduces synaptic BACE1 accumulation by enhancing the removal of BACE1 from distal AD axons and presynaptic terminals. Moreover, elevated Snapin expression via stereotactic hippocampal injections of adeno-associated virus particles in mutant hAPP Tg mouse brains decreases synaptic A␤ levels and ameliorates synapse loss, thus rescuing cognitive impairments associated with hAPP mice. Altogether, our study provides new mechanistic insights into the complex regulation of BACE1 trafficking and presynaptic localization through Snapin-mediated dynein-driven retrograde axonal transport, thereby suggesting a potential approach of modulating A␤ levels and attenuating synaptic deficits in AD.

Regulation of Synaptic Amyloid-β Generation through BACE1 Retrograde Transport in a Mouse Model of Alzheimer's Disease

“…Ye and Cai (2014) recently reported that BACE1 accumulates in late endosomes that cluster at presynaptic terminals of hippocampal neurons in the human APP (hAPP) transgenic mouse model of AD, which produces amyloid pathology in mice comparable to human AD, and in AD patient brains. Given that the lumen of late endosomes is acidic, which is necessary for optimal BACE1 activity (Das et al, 2013), this finding is consistent with the hypothesis that A␤ fragments are produced at the presynaptic terminal within late endosomes (Ye and Cai, 2014;Ye et al, 2017).…”

“…As mentioned previously, postmortem AD patient brains also display accumulations of BACE1-containing late endosomes at presynaptic terminals; however, snapin levels are not altered in either hAPP mice or AD patients (Ye et al, 2017).…”

“…The results from Ye et al (2017) demonstrated that in hAPP mice overexpressing snapin, levels of BACE1-containing late endosomes at the presynaptic terminal were reduced, as evidenced by increased localization of these endosomes in cell bodies, compared with clustering at the presynaptic terminal in control hAPP mice without snapin overexpression. This finding implies that snapin overexpression in hAPP mice reinstates retrograde transport of late endosomes.…”

“…Thus, Ye et al (2017) proposed that overexpressing functional snapin may enhance retrograde transport of BACE1 and thus attenuate production of A␤.…”

“…Because A␤ aggregation and accumulation at presynaptic terminals is hypothesized to be one of the main factors responsible for the cognitive deficits, such as memory loss, present in AD patients (Rajasekhar et al, 2015), Ye et al (2017) hypothesized that snapin overexpression in hAPP mice may lead to improved cognition. Indeed, hAPP mice overexpressing snapin demonstrated significant improvements in nonspatial memory (novel object recognition), spatial memory (shorter latency time in the Morris water maze), and contextual fear conditioning compared with hAPP mice without snapin overexpression.…”