The study investigates the link between amyloid plaques and neurofibrillary tangles in Alzheimer's disease (AD). It demonstrates that tau protein, a microtubule-binding protein, is proteolyzed by multiple caspases at a conserved aspartate residue (Asp421) in its C-terminal region. This cleavage generates a truncated tau protein that assembles more rapidly and extensively into tau filaments compared to wild-type tau. The study shows that this cleavage occurs in neurons treated with amyloid-β (Aβ) peptide and precedes nuclear events of apoptosis. Additionally, the authors find that the truncated tau protein is specifically cleaved at Asp421 in the fibrillar pathologies of AD brain. These findings suggest a novel mechanism where Aβ exposure triggers caspase cleavage of tau, promoting the assembly of pathological tau filaments and linking amyloid deposition to neurofibrillary tangles in AD.The study investigates the link between amyloid plaques and neurofibrillary tangles in Alzheimer's disease (AD). It demonstrates that tau protein, a microtubule-binding protein, is proteolyzed by multiple caspases at a conserved aspartate residue (Asp421) in its C-terminal region. This cleavage generates a truncated tau protein that assembles more rapidly and extensively into tau filaments compared to wild-type tau. The study shows that this cleavage occurs in neurons treated with amyloid-β (Aβ) peptide and precedes nuclear events of apoptosis. Additionally, the authors find that the truncated tau protein is specifically cleaved at Asp421 in the fibrillar pathologies of AD brain. These findings suggest a novel mechanism where Aβ exposure triggers caspase cleavage of tau, promoting the assembly of pathological tau filaments and linking amyloid deposition to neurofibrillary tangles in AD.