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Apolipoprotein E modulates γ‐secretase cleavage of the amyloid precursor protein

Polymorphisms in the apolipoprotein E (APOE) gene affect the risk of Alzheimer disease and the amount of amyloid β‐protein (Aβ) deposited in the brain. The apoE protein reduces Aβ levels in conditioned media from cells in culture, possibly through Aβ clearance mechanisms. To explore this effect, we treated multiple neural and non‐neural cell lines for 24 h with apoE at concentrations similar to those found in the cerebrospinal fluid (1–5 µg/mL). The apoE treatment reduced Aβ40 by 60–80% and Aβ42 to a lesser extent (20–30%) in the conditioned media. Surprisingly, apoE treatment resulted in an accumulation of amyloid precursor protein (APP)‐C‐terminal fragments in cell extracts and a marked reduction of APP intracellular domain‐mediated signaling, consistent with diminished γ‐secretase processing of APP. All three isoforms of apoE, E2, E3 and E4, had similar effects on Aβ and APP‐C‐terminal fragments, and the effects were independent of the low‐density lipoprotein receptor family. Apolipoprotein E had minimal effects on Notch cleavage and signaling in cell‐based assays. These data suggest that apoE reduces γ‐secretase cleavage of APP, lowering secreted Aβ levels, with stronger effects on Aβ40. The apoE modulation of Aβ production and APP signaling is a potential mechanism affecting Alzheimer disease risk.