Model scenarios for cell cycle re-entry in Alzheimer's disease

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease. Aberrant production and aggregation of amyloid beta (A beta) peptide into plaques is a frequent feature of AD, but therapeutic approaches targeting A beta 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.

Automated summary

Alzheimer's disease is the most common neurodegenerative disease characterized by abnormal accumulation and aggregation of amyloid beta peptide. Current treatments can only alleviate symptoms. Research suggests that cell cycle re-entry in neurons may play a crucial role in the disease's progression and severity. This finding provides new insight into potential therapeutic approaches targeting cell cycle re-entry in Alzheimer's disease.