Aging and excitotoxic stress exacerbate neural circuit reorganization in amyloid precursor protein intracellular domain transgenic mice

NEUROBIOLOGY OF AGING

卷:32

Article

Ghosal, Kaushik¹  Pimplikar, Sanjay W.¹ 

[1] Cleveland Clin, Dept Neurosci, Lerner Res Inst, Cleveland, OH 44195 USA

关键词: Alzheimer's disease;    AICD;    Seizure;    Amyloid precursor protein;    Axonal sprouting;    Neuronal network;   

DOI  :  10.1016/j.neurobiolaging.2010.04.020

来源: Elsevier

【 摘 要 】

The cleavage of amyloid precursor protein (APP) by presenilins simultaneously generates amyloid-beta (A beta) and APP intracellular Domain (AICD) peptides. A beta plays a pivotal role in Alzheimer's disease (AD) pathology and recently AICD was also shown to contribute to AD. Transgenic mice overexpressing AICD show age-dependent tau phosphorylation and aggregation, memory deficits, and neurodegeneration. Moreover, these mice show aberrant electrical activity and silent seizures beginning at 3-4 months of age. Here we show that AICD mice also displayed abnormal mossy fiber sprouting beginning about the same time and that this sprouting intensified as the animals aged. Expression of neuropeptide Y was increased in mossy fiber terminals in aged but not young AICD mice. Importantly, young AICD mice injected with kainic acid showed similar pathology to that observed in aged AICD mice. These data show that elevated levels of AICD render neurons hypersensitive to stress and induce hippocampal circuit reorganization, which can further exacerbate hyperexcitability. These results further demonstrate that AICD, in addition to A beta, can play a significant role in AD pathogenesis. (C) 2011 Elsevier Inc. All rights reserved.

【 授权许可】

Free