The cell cycle associated transcription factors mediate neurodegeneration and Trem2 expression in Alzheimer's disease

Abstract

PART I ABSTRACT

Alzheimer’s disease (AD) is a neurological disorder featured by compromised cognitive functions. The mechanistic linkage between the two pathological traits, amyloid plaques and neurofibrillary tangles, has been extensively investigated but still not has not been clarified. Growing studies indicate that amyloid-β (Aβ), the principal component of amyloid plaques, leads to the activation of various mediators of the cell cycle proteins, including Cdks, pRb and transcription factors such as E2F1. Nonetheless, the precise cellular events downstream of Aβ-evoked disturbance of the cell cycle are mostly unidentified. In previous study in our lab and this study, we showed that a cascade of transcription factors including E2F1, c-Myb and Pax6 are intermediate modulators for Aβ-induced cell cycle signals. in a cellular Aβ model. E2F1 mediate neurodegeneration by upregulating transcription factors Pax6 and c-Myb, and Pax6 contributes to the upregulation and activation of GSK-3β, which leads to Tau associated pathophysiology. In summary, cell cycle proteins and associated transcription factors serve as a bridge linking Aβ induction and Tau phosphorylation and aggregation. This study identifies new drug targets for AD therapy.

PART II ABSTRACT Neuroinflammation mediated primarily by microglia has been extensively studied in AD pathogenesis. Through transcriptomic analysis, this study revealed multiple links at transcription level between cell cycle associated transcription factors (E2F1. c-Myb and Pax6) and microglia expressing genes associated with neuroinflammation process in AD development, such as Trem2 and ApoE. Although cell cycle machinery is known to be responsible for cell division and proliferation in microglia activation phase, whether cell cycle proteins participate in the microglia mediated neuroinflammatory process remains largely unknown. In this study, we identified novel cell cycle target genes that are responsible for Trem2 and AP-2 expression. C-Myb can bind to the Trem2 promoter and both c-Myb and Pax6 can bind to AP-2 promoter, and c-Myb binding of Trem2 promoter increases while AP-2 bind of Trem2 promoter decreases upon Aβ insult. More importantly, the transcription links of c-Myb-Trem2 and c-Myb-AP-2 is confirmed in post-mortem AD brains, with increased c-Myb binding of Trem2 promoter and increased c-Myb binding of AP2 promoter. A transcription factor motif analysis revealed that, besides Trem2, the promoter region of many AD-associated microglial genes identified by GWAS studies (ApoE, Sorl1, CLU, ABCA7, SPI1/PU.1, etc,) harbor potential binding sequences of cell cycle related transcription factors. These AD-related genes are involved in various aspects of neuroinflammatory regulation mechanisms in AD. These observations strongly support a cell cycle theory for regulating neuroinflammation in AD pathophysiology. More investigations are still needed to validate this hypothesis.