Abstract
Inhibitor of DNA-binding/differentiation (Id) proteins, a family of helix-loop-helix (HLH) proteins that includes four members of Id1 to Id4 in mammalian cells, are critical for regulating cell growth, differentiation, senescence, cell cycle progression, and increasing angiogenesis and vasculogenesis, as well as accelerating the ability of cell migration. Alzheimer’s disease (AD), the most common neurodegenerative disease in the adult population, manifests the signs of cognitive decline, behavioral changes, and functional impairment. The underlying mechanisms for AD are not well-clarified yet, but the aggregation of amyloid-beta peptides (Aβs), the major components in the senile plaques observed in AD brains, contributes significantly to the disease progression. Emerging evidence reveals that aberrant cell cycle reentry may play a central role in Aβ-induced neuronal demise. Recently, we have shown that several signaling mediators, including Id1, hypoxia-inducible factor-1 (HIF-1), cyclin-dependent kinases-5 (CDK5), and sonic hedgehog (Shh), may contribute to Aβ-induced cell cycle reentry in postmitotic neurons; furthermore, Id1 and CDK5/p25 mutually antagonize the expression/activity of each other. Therefore, Id proteins may potentially have clinical applications in AD. In this review article, we introduce the underlying mechanisms for cell cycle dysregulation in AD and present some examples, including our own studies, to show different aspects of Id1 in terms of cell cycle reentry and other signaling that may be crucial to alter the neuronal fates in this devastating neurodegenerative disease. A thorough understanding of the underlying mechanisms may provide a rationale to make an earlier intervention before the occurrence of cell cycle reentry and subsequent apoptosis in the fully differentiated neurons during the progression of AD or other neurodegenerative diseases.
Highlights
Alzheimer’s disease (AD), a chronic neurodegenerative disorder, is the most common cause of dementia in the aging population
We have shown that Aβ may induce Id1 expression in differentiated rat cortical neurons [32], which contributes to the induction of hypoxia-inducible factor-1 (HIF-1) and the expression of sonic hedgehog (Shh)
The hyperactivity of presenilin (PSEN)-1/2 (PS1/2) and γ-secretase produces abundant Aβs that increase the Id1 expression, which enhances the activation of hypoxia-inducible factor-1α (HIF-1α) and leads to the expression of the sonic hedgehog (Shh) protein; these mediators together contribute to cell cycle reentry with the expression of cell cycle markers such as cyclin D1 and phosphorylated retinoblastoma protein in the postmitotic neurons, which is followed by caspase-3-dependent apoptosis
Summary
Alzheimer’s disease (AD), a chronic neurodegenerative disorder, is the most common cause of dementia in the aging population. Apart from causing neuronal loss, Aβ aggregation activates several transcription factors, such as hypoxia-inducible factor-1 (HIF-1) [4] and nuclear factor-kappa B (NF-κB) [5], to trigger expression of their downstream genes in neurons These gene products may either play a detrimental role contributing to Aβ neurotoxicity [6] or, alternatively, represent an endogenous protective response to counteract the harmful effects from Aβ exposure [7]. Shh mediate cell cycle reentry and apoptosis induced by Aβ in the fully differentiated postmitotic cortical neurons [33] Both Id1 and cyclin-dependent kinase-5 (CDK5) act upstream of HIF-1 to regulate the cell cycle reentry induced by Aβ [34].
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