Amyloid-β (Aβ) peptides play a key role in synaptic damage and memory deficits in the early pathogenesis of Alzheimer's disease (AD). Abnormal accumulation of Aβ at nerve terminals leads to synaptic pathology and ultimately to neurodegeneration. β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the major neuronal β-secretase for Aβ generation. However, the mechanisms regulating BACE1 distribution in axons and β 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 Aβ 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 Aβ levels and attenuating synaptic deficits in AD.SIGNIFICANCE STATEMENT β-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) trafficking and synaptic localization significantly influence its β secretase activity and amyloid-β (Aβ) production. In AD brains, BACE1 is accumulated within dystrophic neurites, which is thought to augment Aβ-induced synaptotoxicity by Aβ overproduction. However, it remains largely unknown whether axonal transport regulates synaptic APP processing. Here, we demonstrate that Snapin-mediated retrograde transport plays a critical role in removing BACE1 from presynaptic terminals toward the soma, thus reducing synaptic Aβ production. Adeno-associated virus-mediated Snapin overexpression in the hippocampus of mutant hAPP mice significantly decreases synaptic Aβ levels, attenuates synapse loss, and thus rescues cognitive deficits. Our study uncovers a new pathway that controls synaptic APP processing by enhancing axonal BACE1 trafficking, thereby advancing our fundamental knowledge critical for ameliorating Aβ-linked synaptic pathology.

Lysosomal proteolysis is essential for the quality control of intracellular components and the maintenance of cellular homeostasis. Lysosomal alterations have been implicated as one of the main cellular defects contributing to the onset and progression of Alzheimer's disease (AD). However, the mechanism underlying lysosomal deficits in AD remains poorly understood. Here, we reveal that lysosomal deficits are attributed to retromer dysfunction induced by altered retromer trafficking in the axon of AD-related mutant human amyloid precursor protein (hAPP) transgenic (Tg) mouse neurons. We demonstrate that retrograde transport of retromer is impaired, leading to its significant reduction in the soma and abnormal retention within late endosomes in distal axons of mutant hAPP neurons. Therefore, retromer-mediated endosome-to-Golgi retrieval of cation-independent mannose-6-phosphate receptors (CI-MPR) in the soma is disrupted in mutant hAPP neurons, causing defects in lysosome biogenesis. Such defects result in protease deficiency in lysosomes and impaired lysosomal proteolysis, as evidenced by aberrant accumulation of sequestered substrates within lysosomes. Intriguingly, enhancement of retrograde transport in mutant hAPP neurons facilitates the trafficking of axonal retromer toward the soma and thus enhances protease transport to lysosomes, thereby restoring lysosomal proteolytic activity. Taken together, our study provides new insights into the regulation of retromer trafficking through retrograde axonal transport to fulfil its function in promoting lysosome biogenesis in the soma, suggesting a potential approach for rescuing lysosomal proteolysis deficits in AD.