Mitochondrial dysfunction is a hallmark of beta-amyloid (Abeta)-induced neuronal toxicity in Alzheimer's disease (AD). Here, we demonstrate that Abeta-binding alcohol dehydrogenase (ABAD) is a direct molecular link from Abeta to mitochondrial toxicity. Abeta interacts with ABAD in the mitochondria of AD patients and transgenic mice. The crystal structure of Abeta-bound ABAD shows substantial deformation of the active site that prevents nicotinamide adenine dinucleotide (NAD) binding. An ABAD peptide specifically inhibits ABAD-Abeta interaction and suppresses Abeta-induced apoptosis and free-radical generation in neurons. Transgenic mice overexpressing ABAD in an Abeta-rich environment manifest exaggerated neuronal oxidative stress and impaired memory. These data suggest that the ABAD-Abeta interaction may be a therapeutic target in AD.

The two current major staging systems in use for Lewy body disorders fail to classify up to 50% of subjects. Both systems do not allow for large numbers of subjects who have Lewy-type α-synucleinopathy (LTS) confined to the olfactory bulb or who pass through a limbic-predominant pathway that at least initially bypasses the brainstem. The results of the current study, based on examination of a standard set of 10 brain regions from 417 subjects stained immunohistochemically for α-synuclein, suggest a new staging system that, in this study, allows for the classification of all subjects with Lewy body disorders. The autopsied subjects included elderly subjects with Parkinson's disease, dementia with Lewy bodies, incidental Lewy body disease and Alzheimer's disease with Lewy bodies, as well as comparison groups without Lewy bodies. All subjects were classifiable into one of the following stages: I. Olfactory Bulb Only; IIa Brainstem Predominant; IIb Limbic Predominant; III Brainstem and Limbic; IV Neocortical. Progression of subjects through these stages was accompanied by a generally stepwise worsening in terms of striatal tyrosine hydroxylase concentration, substantia nigra pigmented neuron loss score, Mini Mental State Examination score and score on the Unified Parkinson's Disease Rating Scale Part 3. Additionally there were significant correlations between these measures and LTS density scores. It is suggested that the proposed staging system would improve on its predecessors by allowing classification of a much greater proportion of cases. KeywordsParkinson's disease; parkinsonism; dementia with Lewy bodies; Alzheimer's disease; incidental Lewy bodies; α-synuclein; olfactory bulb; amgydala; limbic; brainstem; neocortex NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIt has been almost two centuries since the first description (73,74) of Parkinson's disease (PD) and almost one century since the subsequent discovery of its characteristic microscopic lesion, the Lewy body (61,47,82). The intervening years have provided a wealth of detail on its clinical manifestations and pathology. The presenting syndromes are dementia, motor parkinsonism or both. Since Kosaka's delineation of "diffuse Lewy body disease" associated with dementia in 1976(55), followed by the alternative concepts of "senile dementia of the Lewy body type" (78) and "Lewy body variant of Alzheimer's disease" (41), those presenting with dementia are now termed dementia with Lewy bodies (DLB), the definition of which has undergone two major iterations (66,67). In both PD and DLB, aggregation, phosphorylation and nitration of α-synuclein, an abundant synaptic protein, have been suggested to be critical processes leading to Lewy body formation and clinical symptomatology (36,80,28,39,4) .Investigations that have mapped the topographical distribution and density of Lewy bodies and their associated abnormal neurites have indicated that these are spread much more widely throughout the neuraxis than formerly appreciated (22,2...