Aging and excitotoxic stress exacerbate neural circuit reorganization in amyloid precursor protein intracellular domain transgenic mice.
The cleavage of amyloid precursor protein (APP) by presenilins simultaneously generates amyloid-β (Aβ) and APP intracellular Domain (AICD) peptides. Aβ 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 Aβ, can play a significant role in AD pathogenesis.
Ghosal
Kaushik
K
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. ghosalk@ccf.org
Pimplikar
Sanjay W
SW
D000375:Aging / Q000235:genetics / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D007424:Intracellular Fluid / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009415:Nerve Net / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; D018690:Excitatory Amino Acid Agonists