β-Secretase-Cleaved Amyloid Precursor Protein Accumulates at Actin Inclusions Induced in Neurons by Stress or Amyloid β: A Feedforward Mechanism for Alzheimer's Disease

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Abstract
Rod-like inclusions (rods), composed of actin saturated with actin depolymerizing factor (ADF)/cofilin, are induced in hippocampal neurons by ATP depletion, oxidative stress, and excess glutamate and occur in close proximity to senile plaques in human Alzheimer's disease (AD) brain (Minamide et al., 2000). Here, we show rods are found in brains from transgenic AD mice. Soluble forms of amyloid β (Aβ1–42) induce the formation of rods in a maximum of 19% of cultured hippocampal neurons in a time- and concentration-dependent manner. Approximately one-half of the responding neurons develop rods within 6 h or with as little as 10 nmAβ1–42.Aβ1–42induces the activation (dephosphorylation) of ADF/cofilin in neurons that form rods. Vesicles containing amyloid precursor protein (APP), β-amyloid cleavage enzyme, and presenilin-1, a component of the γ-secretase complex, accumulate at rods. The β-secretase-cleaved APP (either β-C-terminal fragment of APP or Aβ) also accumulates at rods. These results suggest that rods, formed in response to either Aβ or some other stress, block the transport of APP and enzymes involved in its processing to Aβ. These stalled vesicles may provide a site for producing Aβ1–42, which may in turn induce more rods in surrounding neurons, and expand the degenerative zone resulting in plaque formation.