Frontal cortical synaptophysin in Lewy body diseases: relation to Alzheimer's disease and dementia

Hansen, Lawrence A.; Daniel, Susan E.; Wilcock, GK; Love, Seth

doi:10.1136/jnnp.64.5.653

Cited by 64 publications

(44 citation statements)

References 22 publications

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“…Loss of synapses is an early and robust correlate of cognitive decline in Alzheimer's disease [11,25], and accumulating evidence point in the direction of the importance of synaptic changes in other dementias as well, including DLB and PDD [8,28,42]. Our work strongly supports this as an exciting area, with potential to improve diagnosis and identify novel therapeutic targets.…”

Section: Conclusion and Future Implicationssupporting

confidence: 64%

Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia

Bereczki

Francis

Howlett

et al. 2016

Alzheimer's & Dementia

144

109

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METHODS: 129 post-mortem human brain samples were analyzed in brain regional specific manner exploring their associations with morphological changes and cognitive decline.RESULTS: We have observed robust changes reflecting synaptic dysfunction in all studied dementia groups. There were significant associations between the rate of cognitive decline and decreased levels of Rab3 in DLB in the inferior parietal lobe and SNAP25 in AD in the prefrontal cortex. Of particular note, synaptic proteins significantly discriminated between dementia cases and controls with over 90% sensitivity and specificity. DISCUSSION: Our findings suggest that the proposition that synaptic markers can predict cognitive decline in AD, should be extended to Lewy body diseases.

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Section: Conclusion and Future Implicationssupporting

confidence: 64%

Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia

Bereczki

Francis

Howlett

et al. 2016

Alzheimer's & Dementia

144

109

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show abstract

“…However, early and more widespread cholinergic losses differentiate DLB from AD. 40 The frequency of associated cerebrovascular lesions in our cohort of DLB was lower than in both PD and control samples (31.6 vs. 36.7 and 33.3.%, respectively). Severe cerebrovascular lesions in DLB were significantly less frequent than in PD and age-matched controls (2.1% vs. 10.8 and 6.4%, respectively), and, in contrast to both groups, no recent ischemic infarct or hemorrhage was reported in the DLB series.…”

Section: S6 Ka Jellingermentioning

confidence: 58%

Neuropathological spectrum of synucleinopathies

Ka¹

2003

Mov Disord.

297

168

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Synucleinopathies comprise a diverse group of neurodegenerative proteinopathies that share common pathological lesions composed of aggregates of conformational and posttranslational modifications of alpha-synuclein in selected populations of neurons and glia. Abnormal filamentous aggregates of misfolded alpha-synuclein protein are the major components of Lewy bodies, dystrophic (Lewy) neurites, and the Papp-Lantos filaments in oligodendroglia and neurons in multiple system atrophy linked to degeneration of affected brain regions. The synucleinopathies include (1) Lewy body disorders and dementia with Lewy bodies, (2) multiple system atrophy (MSA), and (3) Hallervorden-Spatz disease. (1) The pathological diagnosis of Lewy body disorders and dementia with Lewy bodies is established by validated consensus criteria based on semiquantitative assessment of subcortical and cortical Lewy bodies as their common hallmarks. They are accompanied by subcortical multisystem degeneration with neuronal loss and gliosis with or without Alzheimer pathologic state. Lewy bodies also occur in numerous other disorders, including pure autonomic failure, neuroaxonal dystrophies, and various amyloidoses and tauopathies. (2) Multiple system atrophy, a sporadic, adult-onset degenerative movement disorder of unknown cause, is characterized by alpha-synuclein-positive glial cytoplasmic and rare neuronal inclusions throughout the central nervous system associated with striatonigral degeneration, olivopontocerebellar atrophy, and involvement of medullar and spinal autonomic nuclei. (3) In neurodegeneration with brain iron accumulation type I, or Hallervorden-Spatz disease, alpha-synuclein is present in axonal spheroids and glial and neuronal inclusions. While the identity of the major components of Lewy bodies suggests that a pathway leading from normal soluble to abnormal misfolded filamentous proteins is central for their pathogenesis, regardless of the primary disorder, there are conformational differences in alpha-synuclein between neuronal and glial aggregates, showing nonuniform mapping for its epitopes. Despite several cellular and transgenic models, it is not clear whether inclusion body formation is an adaptive/neuroprotective or a pathogenic reaction/process generated in response to different, mostly undetermined, functional triggers linked to neurodegeneration.

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“…For each case, paraffin sections from 10% buffered formalinfixed neocortical, limbic system, and subcortical material stained with hematoxylin and eosin and thioflavin-S were used for routine neuropathological analysis (27) that included Braak stage (28). The diagnosis of DLB was based on the clinical presentation of dementia and the pathological findings of Lewy bodies in the locus coeruleus, substantia nigra, or nucleus basalis of Meynert, as well as in cortical and subcortical regions.…”

Section: Methodsmentioning

confidence: 99%

Direct Transfer of α-Synuclein from Neuron to Astroglia Causes Inflammatory Responses in Synucleinopathies

Lee

Suk²,

Patrick

et al. 2010

Journal of Biological Chemistry

746

726

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Abnormal neuronal aggregation of ␣-synuclein is implicated in the development of many neurological disorders, including Parkinson disease and dementia with Lewy bodies. Glial cells also show extensive ␣-synuclein pathology and may contribute to disease progression. However, the mechanism that produces the glial ␣-synuclein pathology and the interaction between neurons and glia in the disease-inflicted microenvironment remain unknown. Here, we show that ␣-synuclein proteins released from neuronal cells are taken up by astrocytes through endocytosis and form inclusion bodies. The glial accumulation of ␣-synuclein through the transmission of the neuronal protein was also demonstrated in a transgenic mouse model expressing human ␣-synuclein. Furthermore, astrocytes that were exposed to neuronal ␣-synuclein underwent changes in the gene expression profile reflecting an inflammatory response. Induction of pro-inflammatory cytokines and chemokines correlated with the extent of glial accumulation of ␣-synuclein. Together, these results suggest that astroglial ␣-synuclein pathology is produced by direct transmission of neuronal ␣-synuclein aggregates, causing inflammatory responses. This transmission step is thus an important mediator of pathogenic glial responses and could qualify as a new therapeutic target.

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Frontal cortical synaptophysin in Lewy body diseases: relation to Alzheimer's disease and dementia

Cited by 64 publications

References 22 publications

Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia

Synaptic proteins predict cognitive decline in Alzheimer's disease and Lewy body dementia

Neuropathological spectrum of synucleinopathies

Direct Transfer of α-Synuclein from Neuron to Astroglia Causes Inflammatory Responses in Synucleinopathies

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