Pathogenesis of synaptic degeneration in Alzheimer's disease and Lewy body disease

Considerable progress has been made in the past few years in the fight against Alzheimer's disease (AD) and Parkinson's disease (PD). Neuropathological studies in human brains and experimental in vivo and in vitro models support the notion that synapses are affected even at the earliest stages of the neurodegenerative process. The objective of this manuscript is to review some of the mechanisms of synaptic damage in AD and PD. Some lines of evidence support the notion that oligomeric neurotoxic species of amyloid p, a-synuclein, and Tau might contribute to the pathogenesis of synaptic failure at early stages of the diseases. The mechanisms leading to synaptic damage by oligomers might involve dysregulation of glutamate receptors and scaffold molecules that results in alterations in the axonal transport of synaptic vesicles and mitochondria that later on lead to dendritic and spine alterations, axonal dystrophy, and eventually neuronal loss. However, while some studies support a role of oligomers, there is an ongoing debate as to the exact nature of the toxic species. Given the efforts toward earlier clinical and preclinical diagnosis of these disorders, understanding the molecular and cellular mechanisms of synaptic degeneration is crucial toward developing specific biomarkers and new therapies targeting the synaptic apparatus of vulnerable neurons. (C) 2014 Elsevier Inc. All rights reserved.