Amyloid flirting with synaptic failure: Towards a comprehensive view of Alzheimer's disease pathogenesis

Many neurological disorders accompanied by cognitive deficits exhibit abnormal synaptic function. This emerging concept is exemplified by Alzheimer's disease. According to the amyloid hypothesis, Alzheimer's disease is thought to be caused by the progressive accumulation and deposition of neurotoxic Amyloid β-peptide in amyloid plaques and aggregates in brain. Now new theories are emerging associating synaptic and neuronal loss to Amyloid β monomers and Amyloid β oligomers. In particular, Amyloid β oligomers have been described as the earliest effectors to adversely affect synaptic structure and plasticity. In this way, they compromise aspects of learning and memory, including long-term potentiation. Local inflammatory changes, neurofibrillary degeneration, and neurotransmitter deficits all contribute to the memory impairment, but available evidence suggests that these alterations develop as a consequence of early Amyloid β accumulation. Even more recently, different studies have focused on the capability of neuronal activity itself to influence Amyloid Precursor Protein (APP) metabolism. Neuronal activity modulates, in fact, the formation and secretion of Amyloid β peptides. The identification of both the mechanism through which Amyloid β can modify neuronal activity and the way by which neuronal activity can alter APP metabolism is becoming more and more important. And the challenge for the future is, therefore, to find the linkage between these two processes.