{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:39:18Z","timestamp":1790879958356,"version":"4.1.0"},"reference-count":80,"publisher":"Society for Neuroscience","issue":"10","license":[{"start":{"date-parts":[[2017,9,8]],"date-time":"2017-09-08T00:00:00Z","timestamp":1504828800000},"content-version":"vor","delay-in-days":217,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2017,3,8]]},"abstract":"<jats:p>Amyloid-\u03b2 (A\u03b2) peptides play a key role in synaptic damage and memory deficits in the early pathogenesis of Alzheimer's disease (AD). Abnormal accumulation of A\u03b2 at nerve terminals leads to synaptic pathology and ultimately to neurodegeneration. \u03b2-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the major neuronal \u03b2-secretase for A\u03b2 generation. However, the mechanisms regulating BACE1 distribution in axons and \u03b2 cleavage of APP at synapses remain largely unknown. Here, we reveal that dynein\u2013Snapin-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<jats:italic>snapin<\/jats:italic>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\u03b2 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\u03b2 levels and attenuating synaptic deficits in AD.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>\u03b2-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) trafficking and synaptic localization significantly influence its \u03b2 secretase activity and amyloid-\u03b2 (A\u03b2) production. In AD brains, BACE1 is accumulated within dystrophic neurites, which is thought to augment A\u03b2-induced synaptotoxicity by A\u03b2 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 A\u03b2 production. Adeno-associated virus\u2013mediated Snapin overexpression in the hippocampus of mutant hAPP mice significantly decreases synaptic A\u03b2 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 A\u03b2-linked synaptic pathology.<\/jats:p>","DOI":"10.1523\/jneurosci.2851-16.2017","type":"journal-article","created":{"date-parts":[[2017,2,4]],"date-time":"2017-02-04T01:50:27Z","timestamp":1486173027000},"page":"2639-2655","source":"Crossref","is-referenced-by-count":60,"title":["Regulation of Synaptic Amyloid-\u03b2 Generation through BACE1 Retrograde Transport in a Mouse Model of Alzheimer's Disease"],"prefix":"10.1523","volume":"37","author":[{"given":"Xuan","family":"Ye","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4833-2659","authenticated-orcid":false,"given":"Tuancheng","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2963-7473","authenticated-orcid":false,"given":"Prasad","family":"Tammineni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu Young","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2678-4216","authenticated-orcid":false,"given":"David J.","family":"Margolis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaibin","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Kusnecov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8525-2749","authenticated-orcid":false,"given":"Qian","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2017,2,3]]},"reference":[{"key":"2023041803240507000_37.10.2639.1","doi-asserted-by":"publisher","DOI":"10.1002\/cne.901870302"},{"key":"2023041803240507000_37.10.2639.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2012.03.030"},{"key":"2023041803240507000_37.10.2639.3","doi-asserted-by":"publisher","DOI":"10.1007\/BF00308809"},{"key":"2023041803240507000_37.10.2639.4","doi-asserted-by":"publisher","DOI":"10.1002\/bies.201500019"},{"key":"2023041803240507000_37.10.2639.5","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-9-1"},{"key":"2023041803240507000_37.10.2639.6","doi-asserted-by":"publisher","DOI":"10.1038\/85064"},{"key":"2023041803240507000_37.10.2639.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.09.022"},{"key":"2023041803240507000_37.10.2639.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2012.02.005"},{"key":"2023041803240507000_37.10.2639.9","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.10092"},{"key":"2023041803240507000_37.10.2639.10","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M701078200"},{"key":"2023041803240507000_37.10.2639.11","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201412046"},{"key":"2023041803240507000_37.10.2639.12","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2980-05.2005"},{"key":"2023041803240507000_37.10.2639.13","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1459-11.2011"},{"key":"2023041803240507000_37.10.2639.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2003.09.001"},{"key":"2023041803240507000_37.10.2639.15","first-page":"536","article-title":"Design and development of BACE-1 inhibitors","volume":"7","author":"Cumming","year":"2004","journal-title":"Curr Opin Drug Discov Devel"},{"key":"2023041803240507000_37.10.2639.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.05.035"},{"key":"2023041803240507000_37.10.2639.17","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4188"},{"key":"2023041803240507000_37.10.2639.18","first-page":"2.7.1","article-title":"Characterizing synaptic vesicle proteins using synaptosomal fractions and cultured hippocampal neurons","volume":"2","author":"DiGiovanni","year":"2012","journal-title":"Curr Protoc Neurosci"},{"key":"2023041803240507000_37.10.2639.19","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2012.00008"},{"key":"2023041803240507000_37.10.2639.20","unstructured":"Franklin KB , Paxinos G (2001) The mouse brain in stereotaxic coordinates, Ed 2. 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