{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T01:41:59Z","timestamp":1790473319181,"version":"4.1.0"},"reference-count":69,"publisher":"Society for Neuroscience","issue":"42","license":[{"start":{"date-parts":[[2019,4,17]],"date-time":"2019-04-17T00:00:00Z","timestamp":1555459200000},"content-version":"vor","delay-in-days":224,"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":[[2018,10,17]]},"abstract":"<jats:p>Emerging evidences suggest that intraneuronal A\u03b2 correlates with the onset of Alzheimer's disease (AD) and highly contributes to neurodegeneration. However, critical mediator responsible for A\u03b2 uptake in AD pathology needs to be clarified. Here, we report that Fc\u03b3RIIb2, a variant of Fc\u03b3-receptor IIb (Fc\u03b3RIIb), functions in neuronal uptake of pathogenic A\u03b2. Cellular accumulation of oligomeric A\u03b2<jats:sub>1\u201342,<\/jats:sub>not monomeric A\u03b2<jats:sub>1\u201342<\/jats:sub>or oligomeric A\u03b2<jats:sub>1\u201340<\/jats:sub>, was blocked by<jats:italic>Fcgr2b<\/jats:italic>knock-out in neurons and partially in astrocytes. A\u03b2<jats:sub>1\u201342<\/jats:sub>internalization was Fc\u03b3RIIb2 di-leucine motif-dependent and attenuated by TOM1, a Fc\u03b3RIIb2-binding protein that repressed the receptor recycling. TOM1 expression was downregulated in the hippocampus of male 3xTg-AD mice and AD patients, and regulated by miR-126-3p in neuronal cells after exposure to A\u03b2<jats:sub>1\u201342<\/jats:sub>. In addition, memory impairments in male 3xTg-AD mice were rescued by the lentiviral administration of TOM1 gene. Augmented A\u03b2 uptake into lysosome caused its accumulation in cytoplasm and mitochondria. Moreover, neuronal accumulation of A\u03b2 in both sexes of 3xTg-AD mice and memory deficits in male 3xTg-AD mice were ameliorated by forebrain-specific expression of A\u03b2-uptake-defective<jats:italic>Fcgr2b<\/jats:italic>mutant. Our findings suggest that Fc\u03b3RIIb2 is essential for neuropathic uptake of A\u03b2 in AD.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>Accumulating evidences suggest that intraneuronal A\u03b2 is found in the early step of AD brain and is implicated in the pathogenesis of AD. However, the critical mediator involved in these processes is uncertain. Here, we describe that the Fc\u03b3RIIb2 variant is responsible for both neuronal uptake and intraneuronal distribution of pathogenic A\u03b2 linked to memory deficits in AD mice, showing a pathologic significance of the internalized A\u03b2. Further, A\u03b2 internalization is attenuated by TOM1, a novel Fc\u03b3RIIb2-binding protein. Together, we provide a molecular mechanism responsible for neuronal uptake of pathogenic A\u03b2 found in AD.<\/jats:p>","DOI":"10.1523\/jneurosci.1996-17.2018","type":"journal-article","created":{"date-parts":[[2018,9,5]],"date-time":"2018-09-05T17:08:38Z","timestamp":1536167318000},"page":"9001-9018","source":"Crossref","is-referenced-by-count":31,"title":["TOM1 Regulates Neuronal Accumulation of Amyloid-\u03b2 Oligomers by Fc\u03b3RIIb2 Variant in Alzheimer's 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