Elsevier

Neurobiology of Aging

Volume 26, Issue 8, August–September 2005, Pages 1183-1192
Neurobiology of Aging

Aβ deposition is associated with enhanced cortical α-synuclein lesions in Lewy body diseases

https://doi.org/10.1016/j.neurobiolaging.2004.10.006Get rights and content

Abstract

In order to understand better the neuropathological substrate of dementia in Parkinson's disease (PD) and to examine its interactions with Alzheimer's disease (AD), we examined autopsy brains from 21 cases of PD and Lewy body disease (LBD) with dementia. We separated brains in two groups according to the presence of Aβ deposits. In brains without Aβ, we found few or no Lewy bodies (LB) in the cerebral cortex. By contrast, in brains with Aβ, we observed significant increases in LB in the cerebral cortex (p < 0.01) and α-synuclein immunoreactive lesions in the cingulate cortex (p < 0.01). Immunoblots of α-synuclein from cingulate cortex in brains with Aβ showed significantly higher levels of insoluble α-synuclein compared to brains without Aβ.

Our observations indicate that in cases of PD with dementia, the neocortex is not necessarily involved by LB. Furthermore, the presence of Aβ deposits in the cerebral cortex was associated with extensive α-synuclein lesions and higher levels of insoluble α-synuclein. This suggests that Aβ enhances the development of cortical α-synuclein lesions in cases of PD.

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.

Section snippets

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).

References (49)

  • H. Braak et al.

    Pathoanatomy of Parkinson's disease

    J Neurol

    (2000)
  • D.F. Brown et al.

    Neuropathologic evidence that the Lewy body variant of Alzheimer disease represents coexistence of Alzheimer disease and idiopathic Parkinson disease

    J Neuropathol Exp Neurol

    (1998)
  • B.C. Campbell et al.

    The solubility of alpha-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson's disease

    J Neurochem

    (2001)
  • G.C. Cotzias et al.

    L-dopa in Parkinson's syndrome

    N Engl J Med

    (1969)
  • K. Del Tredici et al.

    Where does Parkinson disease pathology begin in the brain?

    J Neuropathol Exp Neurol

    (2002)
  • D.W. Dickson et al.

    Hippocampal degeneration differentiates diffuse Lewy body disease (DLBD) from Alzheimer's disease: light and electron microscopic immunocytochemistry of CA2-3 neurites specific to DLBD

    Neurology

    (1991)
  • D.W. Dickson

    Alpha-synuclein and the Lewy body disorders

    Curr Opin Neurol

    (2001)
  • J.E. Duda et al.

    Immunohistochemical and biochemical studies demonstrate a distinct profile of alpha-synuclein permutations in multiple system atrophy

    J Neuropathol Exp Neurol

    (2000)
  • L.S. Forno

    Neuropathology of Parkinson's disease

    J Neuropathol Exp Neurol

    (1996)
  • B.I. Giasson et al.

    Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions

    Science

    (2000)
  • B.I. Giasson et al.

    Initiation and synergistic fibrillization of tau and alpha-synuclein

    Science

    (2003)
  • M. Goedert

    Alpha-synuclein and neurodegenerative diseases

    Nat Rev Neurosci

    (2001)
  • H.J. Gundersen et al.

    Some new, simple and efficient stereological methods and their use in pathological research and diagnosis

    APMIS

    (1988)
  • K. Gwinn-Hardy et al.

    Distinctive neuropathology revealed by alpha-synuclein antibodies in hereditary Parkinsonism and dementia linked to chromosome 4p

    Acta Neuropathol (Berl)

    (2000)
  • Cited by (184)

    • Biophysical processes underlying cross-seeding in amyloid aggregation and implications in amyloid pathology

      2021, Biophysical Chemistry
      Citation Excerpt :

      However, we are just starting to understand the processes causing α-synuclein to act differently. In support of proteopathic cross-seeding is the observation that the ultrastructure and the pattern of distribution of the ‘mixed’ pathologies changes compared to the single-pathology cases [122,125,132]. Additionally, the seeding capability of α-synuclein depends on its multimerization state, as monomeric α-synuclein slows and prevents the aggregation of Aβ [95,133] and prion protein [134], while oligomeric α-synuclein nucleates the aggregation of Aβ and prion protein [27,37,49,95,122–127].

    View all citing articles on Scopus
    1

    Tel.: +1 410 9555632; fax: +1 410 9559777.

    View full text