Epigenetic Shifts Reveal Alzheimer's Origins after Sustained Picomolar Aβ Exposure
Paquola, A.; Acquarone, E.; Staniszewski, A.; Teich, A. F.; Arancio, O.
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Recent advances in sequencing have identified genetic risk factors for Alzheimers disease (AD), but the molecular mechanisms triggering disease onset remain unclear. While high brain levels of amyloid-beta (A{beta}) impair synaptic function and memory, exposure to low picomolar (pM) A{beta} concentrations - typical of healthy brains - enhances these functions, while sustained exposure results in impairment. To investigate this transition from physiological to pathological A{beta} activity, we profiled DNA methylation and gene expression in C57B16 mice subjected to prolonged pM A{beta}42 exposure. We identified differentially methylated and expressed genes, including those involved in synaptic function, associated with three phases: memory enhancement (brief exposure), a transitional state with intact memory (intermediate), and memory decline (prolonged). These gene sets may represent early molecular drivers of AD pathogenesis.
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