Tau-dependent microtubule disassembly initiated by prefibrillar β-amyloid

Alzheimer's Disease (AD) is defined histopathologically by extracellular p-amyloid (A beta) fibrils plus intraneuronal tau filaments. Studies of transgenic mice and cultured cells indicate that AD is caused by a pathological cascade in which A beta lies upstream of tau, but the steps that connect A beta to tau have remained undefined. We demonstrate that tau confers acute hypersensitivity of microtubules to prefibrillar, extracellular A beta in nonneuronal cells that express transfected tau and in cultured neurons that express endogenous tau. Prefibrillar A beta 42 was active at submicromolar concentrations, several-fold below those required for equivalent effects of prefibrillar A beta 40, and microtubules were insensitive to fibrillar A beta. The active region of tau was localized to an N-terminal domain that does not bind microtubules and is not part of the region of tau that assembles into filaments. These results suggest that a seminal cell biological event in AD pathogenesis is acute, tau-dependent loss of microtubule integrity caused by exposure of neurons to readily diffusible A beta.