Aβ deposition is associated with enhanced cortical α-synuclein lesions in Lewy body diseases
Introduction
Lewy body diseases (LBD) encompass three main clinicopathological syndromes associated with α-synuclein lesions: Parkinson's disease (PD); dementia with Lewy bodies (DLB), and primary autonomic failure [37]. PD is clinically characterized by bradykinesia, resting tremor, rigidity, gait abnormalities, and postural instability [40]. Although the initial clinical manifestations of PD are predominantly motor, patients frequently develop cognitive decline and dementia as the disease progresses. When motor impairment precedes cognitive decline a year or longer, these patients are classified as PD with dementia [36]. Indeed, since the introduction of therapy with L-DOPA in the 1960s [9], patients with PD survive for many years after the onset of motor manifestations and the frequency of dementia may reach as high as 80% among those with eight or more years of disease duration [1], [29], [32]. Pathologically, PD is characterized by the degeneration of dopaminergic neurons of the substantia nigra and other subcortical structures, and the presence of α-synuclein enriched Lewy bodies (LB) and Lewy neurites (LN) [6], [12], [14], [17].
DLB is characterized primarily by fluctuating cognitive impairment, attentional deficits, visual hallucinations, and extrapyramidal manifestations. Pathologically, DLB is characterized by LB and LN of variable severity throughout the cerebral cortex, limbic structures, and brain stem [36], [37].
LB are spherical, intracytoplasmic, eosinophilic inclusions that contain intermediate filament proteins, ubiquitin, and α-synuclein [46]. The presence of mutations of the α-synuclein gene in kindreds with familial PD supports a role for this protein in the pathogenesis of PD [42]. The pathologic process leading to the aggregation and accumulation of α-synuclein in neurons and neurites is not known, but one appealing hypothesis is that abnormal post-translational modifications of α-synuclein, such as oxidative damage [15], [39], [41], [43], phosphorylation [26], and/or truncation [31] promote the formation of insoluble aggregates. The degeneration of the substantia nigra and its projection to the striatum is accepted as the substrate of the motor abnormalities in PD, but there is no similar consensus regarding the morphological substrate of dementia in this disorder. Although lesions in various brain regions have been associated with the dementia of PD, in particular LB and LN of the CA2–3 region of the hippocampus [11] and cortical LB [30], [44], the precise pathological substrate of dementia in these patients remains elusive [2], [4], [23], [24]. The identification of the lesions responsible for dementia in PD has been hindered by biological and technical factors. PD frequently coexists with Alzheimer's disease (AD) [7], [25], [34], [35], the most common cause of dementia in older subjects, and until recently it has been difficult to discern histologically between the lesions of these two common disorders. Before the advent of α-synuclein antibodies in 1997 [46] immunostaining for ubiquitin was the method of choice to detect LB and LN; however, since the lesions of AD (i.e., senile plaques, neurofibrillary tangles, and dystrophic neurites) are also ubiquitin(+) it was very difficult to separate the histological lesions of the two disorders. In the present study, we use immunostains of α-synuclein, Aβ and tau, specific markers for the lesions and abnormal proteins of PD and AD, and biochemical analyses of α-synuclein to search for the substrate of dementia in PD and to examine the interactions between the two disorders.
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Subjects
We examined brain tissues from all cases of LBD with dementia (n = 21) autopsied at the Johns Hopkins Hospital between 1991 and 2002. Under this diagnosis, we include 18 cases of PD and three cases of LBD with dementia. These cases were from the JHU Parkinson's Disease Research Center, the Alzheimer's Disease Research Center, and from the Department of Neurology. The cases included 18 males and 3 females, with an age range between 64 and 90 years and an average age of 77 years. The duration of
α-Synuclein immunostaining enhancement by pretreatment with formic acid
As a technical preamble to our studies, we found that pretreatment with formic acid greatly enhanced the immunoreactivity (IR) for α-synuclein in all regions of the brain examined. This enhancement was particularly remarkable in the CA2 region of the hippocampus, where we measured a 13-fold increase in IR with formic acid pretreatment of the tissue sections (p < 0.01).
α-Synuclein lesions: Lewy bodies and neurites
Neuropathological examination of all cases revealed α-synuclein lesions in the form of LB and LN of variable severity throughout
Discussion
The first observation of our study is that formic acid pretreatment of α-synuclein immunostains [47] yields an enhancement of one order of magnitude and provides for a superior assessment of lesions. This enhancement can be explained by formic acid unmasking of epitopes in a protein that has become aggregated, similar to the effect of formic acid on Aβ immunostains. It may be worthwhile to consider the enhancement of α-synuclein immunostains, by formic acid or proteinases [25], [27], [47] as
Acknowledgements
We would like to thank Ms. Marylin Peper for her excellent technical assistance, and Ms. Audrey Horter for preparing the manuscript. This work was supported by the Morris K. Udall Parkinson's Disease Research Center of Excellence (NINDS grant NS038377), the Alzheimer's Disease Research Center (NIA grant AG 05146), NINDS grant NS38065 (MKL) and a grant from American Health Assistance Foundation (MKL).
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