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• W4207046992 abstract "Abstract The small Aβ peptide has been hypothesized to be the main driver of Alzheimer’s disease (AD). Aβ is a proteolytic cleavage product of a larger protein, the amyloid precursor protein (APP), whose normal functions remain largely unexplored. We report here activities of the full-length APP protein that relate directly to the etiology of AD. Increasing neuronal activity leads to a rapid increase in App gene expression. In both cultures of mouse cortical neurons and human iPSC-derived neurons, elevated APP protein changes the structure of the axon initial segment (AIS), the site of action potential initiation. In neurons with elevated APP, the AIS shortens in length and shifts in position away from the cell body. Both changes would be expected to reduce neuronal excitability. The AIS effects are due to the cell-autonomous actions of APP; exogenous Aβ – either fibrillar or oligomeric – has no effect. The findings relate directly to AD in several ways. In culture, APP carrying the Swedish familial AD mutation (APP Swe ) induces stronger AIS changes than wild type APP. Ankyrin G and βIV-spectrin, scaffolding proteins of the AIS, both physically associate with APP, and APP Swe binds more avidly than wild type APP. Finally, neurons in the frontal cortex of humans with sporadic AD reveal histologically elevated levels of APP protein that invade the domain of the AIS, whose length is significantly shorter than that found in healthy control neurons. The findings offer an alternative explanation for the effects of at least some familial AD mutations. Significance In familial Alzheimer’s disease (AD) the linkage between the genetics of APP, the neuropathology of the amyloid plaques and the symptoms of dementia are one of the strongest pieces of evidence supporting the amyloid cascade hypothesis – a conceptualization that marks the Aβ peptide as the root cause of AD. Yet, formally, the genetics only point to APP, not its Aβ breakdown product. We report here that the full-length APP protein affects the properties of the axon initial segment and through these changes serves as a dynamic regulator of neuronal activity. We propose that this newly discovered APP function offers a different, Aβ-independent, view of the genetic evidence." @default.
• W4207046992 created "2022-01-26" @default.
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• W4207046992 date "2022-01-24" @default.
• W4207046992 modified "2023-10-01" @default.
• W4207046992 title "The amyloid precursor protein modulates the position and length of the axon initial segment offering a new perspective on Alzheimer’s disease genetics" @default.
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• W4207046992 doi "https://doi.org/10.1101/2022.01.23.477413" @default.
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