Abstract
Accumulating evidence suggests that neurons prone to degeneration in Alzheimer's Disease (AD) exhibit evidence of re-entry into an aberrant mitotic cell cycle. Our laboratory recently demonstrated that, in a genomic amyloid precursor protein (APP) mouse model of AD (R1.40), neuronal cell cycle events (CCEs) occur in the absence of beta-amyloid (Aβ) deposition and are still dependent upon the amyloidogenic processing of the amyloid precursor protein (APP). These data suggested that soluble Aβ species might play a direct role in the induction of neuronal CCEs. Here, we show that exposure of non-transgenic primary cortical neurons to Aβ oligomers, but not monomers or fibrils, results in the retraction of neuronal processes, and induction of CCEs in a concentration dependent manner. Retraction of neuronal processes correlated with the induction of CCEs and the Aβ monomer or Aβ fibrils showed only minimal effects. In addition, we provide evidence that induction of neuronal CCEs are autonomous to primary neurons cultured from the R1.40 mice. Finally, our results also demonstrate that Aβ oligomer treated neurons exhibit elevated levels of activated Akt and mTOR (mammalian Target Of Rapamycin) and that PI3K, Akt or mTOR inhibitors blocked Aβ oligomer-induced neuronal CCEs. Taken together, these results demonstrate that Aβ oligomer-based induction of neuronal CCEs involve the PI3K-Akt-mTOR pathway.
Highlights
Alzheimer's disease (AD) is the most common form of senile dementia and is a leading cause of disability and death [1,2]
Synthetic Aβ peptides were aged for various amounts of time in phosphate buffer followed by sizeexclusion column (SEC) fractionation, yielding two major peaks corresponding to Aβ oligomers (AβO) and Aβ monomers (AβM), with Aβ oligomers eluting at 12–15 min and Aβ monomers eluting at 25–30 min
Exposure to Aβ monomers did not exhibit the same increase in the levels of Proliferative Cellular Nuclear Antigen (PCNA). These results demonstrate that purified preparations of stable Aβ oligomers induce cycle events (CCEs) in primary cortical neurons in a concentration dependent manner that is not observed with preparations of Aβ monomers or Aβ fibrils
Summary
Alzheimer's disease (AD) is the most common form of senile dementia and is a leading cause of disability and death [1,2]. A definitive diagnosis of AD requires the demonstration of distinctive brain pathology, including extracellular deposits of the beta-amyloid (Aβ) peptide in senile plaques and intracellular aggregates of the microtubule-associated protein, tau, in neurofibrillary tangles. Another invariant feature of the disease includes substantial neuronal cell loss in discrete brain regions, the mechanisms underlying the neurodegeneration remain unclear. We recently reported that neuronal CCEs in the R1.40 mouse model occur in the absence of Aβ deposition and yet are dependent upon the amyloidogenic processing of the APP by beta-secretase [9,11]. The exact nature of the neurotoxic substance is still unknown
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