Tau-dependent microtubule disassembly initiated by prefibrillar [beta]-amyloid

Alzheimer's Disease (AD) is defined histopathologically by extracellular [beta]-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].