期刊
JOURNAL OF NEUROSCIENCE
卷 25, 期 49, 页码 11313-11321出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3711-05.2005
关键词
ADF/cofilin; actin; neurite inclusions; Alzheimer's disease; transport; APP processing; amyloid beta
资金
- NIGMS NIH HHS [R01 GM035126, GM35126] Funding Source: Medline
- NINDS NIH HHS [T32 NS043115, NS40371, R01 NS040371, NS43115] Funding Source: Medline
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 beta (alpha beta 1-42) 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 nm A beta(1-42). A beta 1-42 induces the activation (dephosphorylation) of ADF/cofilin in neurons that form rods. Vesicles containing amyloid precursor protein (APP), beta-amyloid cleavage enzyme, and presenilin-1, a component of the gamma-secretase complex, accumulate at rods. The beta-secretase-cleaved APP (either beta-C-terminal fragment of APP or A beta) also accumulates at rods. These results suggest that rods, formed in response to either A beta or some other stress, block the transport of APP and enzymes involved in its processing to A beta. These stalled vesicles may provide a site for producing A beta(1-42), which may in turn induce more rods in surrounding neurons, and expand the degenerative zone resulting in plaque formation.
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