Neurobiology of Disorders with Lewy Bodies

Lewy body disease (LBD) and Alzheimer's disease (AD) continue to be the most common disorders causing dementia in the elderly population. Disorders with Lewy bodies comprise a diverse group of diseases. A consensus paper by McKeith and others has proposed comprehensive criteria in an attempt to reconcile the disagreements within the current terminology. Although the precise cause of these disorders is currently unknown, neuropathologically the common denominator is the degeneration of neuronal populations within the nigral dopaminergic system and mesial temporal regions, LB formation, extensive neuritic degeneration, and spongiform vacuolization. Previous studies have shown that cognitive alterations in these disorders are associated with synaptic damage. Injury to the synapse may be associated with an altered function of synaptic proteins. Among them, studies have shown that abnormal aggregation and accumulation of synaptic proteins such as α-synuclein (or the precursor of the non-Aβ component of AD amyloid, NACP) may be associated with plaque formation in AD and Lewy body formation in LBD. Further reinforcing the argument that α-synuclein plays a major role in the pathogenesis of these disorders, work has shown that mutations which alter the conformation of this molecule are associated with familial forms of LBD and that α-synuclein is a major component of Lewy bodies. The mechanisms by which altered function or aggregation of α-synuclein leads to neurodegeneration are not completely clear; however, new evidence points to a potential role for this molecule in synaptic damage and neurotoxicity via amyloid fibril formation and mitochondrial dysfunction. This chapter reviews data linking α-synuclein to the pathogenesis of LBD.