The Role of Amyloid-Beta and Tau in the Early Pathogenesis of Alzheimer's Disease.

Abstract

The abnormal accumulation of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) containing phosphorylated tau proteins are the main histopathological feature of Alzheimer’s disease (AD). Synaptic damage and loss are earlier events than amyloid plaques and NFTs in AD progress and best correlate with cognitive deficits in AD patients. Soluble oligomeric Aβ initiates the progression of AD and tau mediates the subsequent synaptic impairments at an early stage of AD. In this review we discuss how Aβ or/and tau causes synaptic dysfunction. Aβ oligomers gather at synapses and give rise to synaptic death in a variety of ways such as regulating receptors and receptor tyrosine kinases, unbalancing calcium homeostasis, and activating caspases and calcineurin. A large amount of hyperphosphorylated tau exists in the synapse of the AD brain. Aβ-triggered synaptic deficits are dependent on tau. Soluble, hyperphosphorylated tau is much more correlated to cognitive decline in AD patients. Tau-targeted therapies have received more attention because the treatments targeting Aβ failed in AD. Here, we also review the therapy strategies used to intervene in the very early stages of AD. Soluble hyperphosphorylated tau forms a complex with cell surface receptors, scaffold proteins, or intracellular signaling molecules to damage synaptic function. Therefore, therapeutic strategies targeting synaptic tau at the early stage of AD may ameliorating pathology in AD. This review aims to provide an update on the role of oligomeric Aβ and soluble hyperphosphorylated tau in the early pathogenesis of Alzheimer’s disease and to develop a new treatment strategy based on this.