Summary

Cortical Lewy bodies are the defining pathological feature of Lewy body dementia. Ultrastructural, immunocytochemical and direct biochemical analysis confirm that Lewy bodies represent intraneuronal perikaryal accumulations of phosphorylated neurofilament proteins. Lewy bodies are thus a marker that the normal architecture of the neuronal cytoskeleton is disrupted.

Considerable evidence points to cytoskeletal disruption as a constituent part of the molecular pathogenesis of neurodegeneration. In terms of these cytoskeletal-related changes, Lewy body diseases appear to result from a disorder of neurofilament accumulation, in contrast to Alzheimer's disease in which the microtubule-associated protein, tau, accumulates. The two diseases appear to be distinct at a molecular level and evidence is amassing for a distinction at the genetic level. It seems that for both Alzheimer's disease and Lewy body dementia phosphorylation of cytoskeletal proteins is altered.

Experimental models have shown that changes in expression of neurofilaments lead to disruption of neurofilament assembly, neurofilament pathology and neuronal loss. Evidence is reviewed here that changes in neurofilament processing are intrinsic to the neurodegenerative process in Lewy body dementia.

Introduction

Alzheimer's disease (AD) is characterized by the pathological lesions of amyloid plaques and neurofibrillary tangles. In addition to plaques and tangles however, AD brains often contain cortical Lewy bodies which are also found in a subset of dementia patients with relatively few or even no discernible tangles. Neurofibrillary tangles are composed principally of abnormally phosphorylated tau assembled into paired helical filaments (PHF-tau), structures not confined to intracellular tangles but widely distributed in the brain as neuropil threads, extracellular tangles and in plaque associated neurites. How do these pathological lesions relate to each other – if at all?