Lewy Bodies Contain Altered α-Synuclein in Brains of Many Familial Alzheimer's Disease Patients with Mutations in Presenilin and Amyloid Precursor Protein Genes

Lippa, Carol F.; Fujiwara, Hideo; Mann, David; Giasson, Benoit I.; M, Baba; Schmidt, Maria Luiza Gava; Nee, Linda E.; O’Connell, Brendan P.; Pollen, Daniel A.; George‐Hyslop, Peter St; Ghetti, Bernardino; Nochlin, David; Bird, Thomas D.; Cairns, Nigel J.; Lee, Virginia M.‐Y.; Iwatsubo, Takeshi; Trojanowski, John Q.

doi:10.1016/s0002-9440(10)65722-7

Cited by 466 publications

(280 citation statements)

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“…The mechanism by which these variants cause disease is by altering ␥-secretase activity in a manner that elevates the ratio of ␤-amyloid (A␤) 42/40 peptides, thus enhancing nucleation and fibrillogenesis of highly amyloidogenic A␤ 42 (Bentahir et al, 2006;Kumar-Singh et al, 2006). Although the neuropathological features of patients with FADlinked PSEN1 mutations include the presence of senile plaques, composed primarily of A␤, and degenerating neurons containing hyperphosphorylated tau, the coexistence of Lewy bodies (LBs), composed primarily of ␣-synuclein filaments, is becoming increasingly evident (Lippa et al, 1998;Rosenberg, 2005;Leverenz et al, 2006). In addition, the phosphorylation of ␣-synuclein at Ser-129, identified as a major modification of ␣-synuclein, is now considered to be the key event responsible for the formation of LBs and Lewy neurites (Fujiwara et al, 2002;Anderson et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Enhanced Accumulation of Phosphorylated α-Synuclein and Elevated β-Amyloid 42/40 Ratio Caused by Expression of the Presenilin-1 ΔT440 Mutant Associated with Familial Lewy Body Disease and Variant Alzheimer's Disease

Kaneko¹,

Kakita²,

Kasuga³

et al. 2007

J. Neurosci.

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Mutations in the PSEN1 gene encoding presenilin 1 (PS1) are linked to a vast majority of pedigrees with early-onset, autosomal dominant forms of familial Alzheimer's disease (FAD). Lewy body (LB) pathology is frequently found in the brains of FAD patients harboring PSEN1 mutations. We recently reported on a novel PS1 mutation with the deletion of threonine at codon 440 (⌬T440) in a familial case diagnosed as having the neocortical type of dementia with LBs (DLB) and variant AD. In this report, we investigated the possible involvement of PS1 ⌬T440 mutation in aberrant ␣-synuclein accumulation. We established cell lines that stably express either wild-type (WT) PS1 or the FAD-linked PS1 H163R, E280A, ⌬E9, and PS1 ⌬T440 mutants and now demonstrate that the expression of the PS1 ⌬T440 mutant led to a marked elevation in the ratio of ␤-amyloid (A␤) 42/40 peptides in a conditioned medium. More importantly, we report here that the levels of phosphorylated ␣-synuclein increase in neuronal and non-neuronal cells expressing the PS1 ⌬T440 mutant compared with cells that express WT PS1 or the PS1 H163R and E280A variants that are not associated with LB pathology. This finding is consistent with our demonstration of elevated levels of phosphorylated ␣-synuclein in the detergent-resistant fraction prepared from a patient's brain with PS1 ⌬T440 mutation. These observations raise the intriguing suggestion that the mechanism(s) by which the PS1 ⌬T440 mutant causes DLB and variant AD are by enhancing the phosphorylation of ␣-synuclein and the ratio of A␤ 42/40 peptides, respectively, in the brain.

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Section: Introductionmentioning

confidence: 99%

Enhanced Accumulation of Phosphorylated α-Synuclein and Elevated β-Amyloid 42/40 Ratio Caused by Expression of the Presenilin-1 ΔT440 Mutant Associated with Familial Lewy Body Disease and Variant Alzheimer's Disease

Kaneko¹,

Kakita²,

Kasuga³

et al. 2007

J. Neurosci.

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“…For example, the postmortem brains of individuals with familial AD (EAD) due to autosomal dominant mutations in the Presenilin 1, Presenilin 2 or the Ab precursor protein genes contain variable numbers of a-synuclein positive LBs, especially in the amygdala (Lippa et al, 1998). Notably, LBs also are abundant in the amygdala of patients with sporadic AD (Schmidt et al, 1996).…”

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confidence: 99%

Fatal attractions: abnormal protein aggregation and neuron death in Parkinson's disease and Lewy body dementia

et al. 1998

Self Cite

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The abnormal aggregation of proteins into fibrillar lesions is a neuropathological hallmark of several sporadic and hereditary neurodegenerative diseases. For example, Lewy bodies (LBs) are intracytoplasmic filamentous inclusions that accumulate primarily in subcortical neurons of patients with Parkinson's disease (PD), or predominantly in neocortical neurons in a subtype of Alzheimer's disease (AD) known as the LB variant of AD (LBVAD) and in dementia with LBs (DLB). Aggregated neurofilament subunits and a-synuclein are major protein components of LBs, and these inclusions may contribute mechanistically to the degeneration of neurons in PD, DLB and LBVAD. Here we review recent studies of the protein building blocks of LBs, as well as the role LBs play in the onset and progression of PD, DLB and LBVAD. Increased understanding of the protein composition and pathological significance of LBs may provide insight into mechanisms of neuron dysfunction and death in other neurodegenerative disorders characterized by brain lesions containing massive deposits of proteinacious fibrils.

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“…This conclusion was supported by data which demonstrated that although protease resistant, tau-immunoreactive paired helical filaments (PHF) were a feature of AD, only very low densities were found in DLB [66]. In addition, Aβ pathology, neuritic plaques (NP), NFT, and neuropil threads (NT) were studied in control subjects, DLB and AD and it was concluded that apart from the common feature of diffuse plaques, pure DLB and AD were distinct disorders [89]. Similarly, Kawanishi et al [78] concluded that DLB and AD were distinct disorders but with a common mechanism with reference to amyloid formation.…”

Section: Aβ Depositsmentioning

confidence: 86%

“…This conclusion was also reached by Trojanowski and Lee [136] who argued that the biological significance of the LB was therefore unclear. In addition, Lippa et al [89] found that α-synucleinimmunoreactive LB were present in 22% of cases of familial AD and were most numerous in the amygdala where they coexisted with tau-immunoreactive NFT. Similarly, in a study by Rosenberg et al [122] of an AD family linked to an APP 717 mutation, one individual had the limbic form of DLB, two had neocortical DLB, and other members of the family had no LB.…”

Section: Tau-immunoreactive Lesionsmentioning

confidence: 99%

“…In addition, Arai et al [3] emphasised that AD and PD share many common clinical and pathological features, α-synuclein-immunoreactive lesions being observed in 27 cases of AD. Some DS cases may also possess α-synuclein-immunoreactive inclusions and a number of cases have been reported with both LB and α-synuclein-immunoreactive dystrophic neurites [89]. Moreover, 50% of cases in which LB were present in the amygdala also possessed AD-type changes elsewhere in the cerebral cortex.…”

Section: Tau-immunoreactive Lesionsmentioning

confidence: 99%

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On the ‘classification’ of neurodegenerative disorders: discrete entities, overlap or continuum?

Armstrong¹

2012

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A b s t r a c t ('overlap' model) , and (3) that distinct diseases do not exist and neurodegenerative disease is a 'continuum' in which there is continuous variation in clinical/pathological features from one case to another ('continuum' model). Third, to distinguish between models, the distribution of the most important molecular 'signature' lesions across the different diseases is reviewed. Such lesions often have poor

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Lewy Bodies Contain Altered α-Synuclein in Brains of Many Familial Alzheimer's Disease Patients with Mutations in Presenilin and Amyloid Precursor Protein Genes

Cited by 466 publications

References 28 publications

Enhanced Accumulation of Phosphorylated α-Synuclein and Elevated β-Amyloid 42/40 Ratio Caused by Expression of the Presenilin-1 ΔT440 Mutant Associated with Familial Lewy Body Disease and Variant Alzheimer's Disease

Enhanced Accumulation of Phosphorylated α-Synuclein and Elevated β-Amyloid 42/40 Ratio Caused by Expression of the Presenilin-1 ΔT440 Mutant Associated with Familial Lewy Body Disease and Variant Alzheimer's Disease

Fatal attractions: abnormal protein aggregation and neuron death in Parkinson's disease and Lewy body dementia

On the ‘classification’ of neurodegenerative disorders: discrete entities, overlap or continuum?

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