Why did we evolve to suffer excess amyloid-β deposition in the brain in later life? The disruptive basis for Alzheimer’s disease lies in misfolded amyloid-β accumulating over decades. According to the antagonistic pleiotropy viewpoint, processes advantageous in youth can also cause harm in old age due to stronger selection pressure on the young. Despite the harm it causes later in life, amyloid-β serves as an antimicrobial peptide in the innate immune system. This benefit to younger individuals has kept it in our systems over time.
In Alzheimer’s Disease, amyloidogenic proteins like β-amyloid and tau may trigger neuroinflammation and cell death. Immune networks, particularly type 2 components, play a specialized role in brain function. Imbalance in immune surveillance can lead to decreased amyloid clearance, synaptic loss, and neurodegeneration. This abnormal immune response and inflammation can further exacerbate damage. The reasons for maintaining these harmful conditions throughout evolution are unclear.
The concept of amyloidogenic evolvability (aEVO) suggests that AP aggregates may have evolved as an adaptation to environmental stress. The interaction between AP aggregation and neuroinflammation may promote AD pathogenesis through antagonistic pleiotropy. Targeting both AP aggregation and specific neuroinflammatory pathways could improve AD therapeutics. Understanding innate neuroimmunity and aEVO could lead to better diagnostics and treatments for AD.
Link: https://doi.org/10.3389/fcell.2024.1430593
