Pandey_2022_iScience_25_104543

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease. Aberrant production and aggregation of amyloid beta (Abeta) peptide into plaques is a frequent feature of AD, but therapeutic approaches targeting Abeta accumulation fail to inhibit disease progression. The approved cholinesterase inhibitor drugs are symptomatic treatments. During human brain development, the progenitor cells differentiate into neurons and switch to a postmitotic state. However, cell cycle re-entry often precedes loss of neurons. We developed mathematical models of multiple routes leading to cell cycle re-entry in neurons that incorporate the crosstalk between cell cycle, neuronal, and apoptotic signaling mechanisms. We show that the integration of multiple feedback loops influences disease severity making the switch to pathological state irreversible. We observe that the transcriptional changes associated with this transition are also characteristics of the AD brain. We propose that targeting multiple arms of the feedback loop may bring about disease-modifying effects in AD.