Tau and α-Synuclein Pathology in Amygdala of Parkinsonism-Dementia Complex Patients of Guam

Abstract

Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disorder of Chamorro residents of Guam and the Mariana Islands, characterized by abundant neuron loss and tau neurofibrillary pathology similar to that observed in Alzheimer's disease (AD). A variety of neurodegenerative diseases with tau pathology including ALS/PDC also have alpha-synuclein positive pathology, primarily in the amygdala. We further characterized the tau and alpha-synuclein pathology in the amygdala of a large series of 30 Chamorros using immunohistochemical and biochemical techniques. Tau pathology was readily detected in both affected and unaffected Chamorros. In contrast, alpha-synuclein pathology was detected in 37% of patients with PDC but not detected in Chamorros without PDC or AD. The alpha-synuclein aggregates often co-localized within neurons harboring neurofibrillary tangles suggesting a possible interaction between the two proteins. Tau and alpha-synuclein pathology within the amygdala is biochemically similar to that observed in AD and synucleinopathies, respectively. Thus, the amygdala may be selectively vulnerable to developing both tau and alpha-synuclein pathology or tau pathology may predispose it to synuclein aggregation. Furthermore, in PDC, tau and alpha-synuclein pathology occurs independent of beta-amyloid deposition in amygdala thereby implicating the aggregation of these molecules in the severe neurodegeneration frequently observed in this location.

Quantitative Proteomics Identifies Surfactant-Resistant α-Synuclein in Cerebral Cortex of Parkinsonism-Dementia Complex of Guam but Not Alzheimer's Disease or Progressive Supranuclear Palsy

“…One group used an extraction protocol similar to ours to show insoluble forms of SNCA in the amygdala only in those PDC patients with SNCA-immunoreactive inclusions. 55 In contrast to these findings in regions of brain with unclear relevance to the clinical manifestations of PDC, our quantitative data demonstrated the accumu- lation of abnormally hydrophobic SNCA in frontal and temporal cortex of patients with PDC to levels comparable with DLB despite the lack of LB accumulation in these regions of brain that are clearly related to cognitive function. Others have presented elegant data demonstrating interactions between SNCA and tau 57 ; however, we think this is an unlikely explanation for PDC because although AD, PSP, and PDC had increased SI and TI tau, only PDC had significantly increased TI SNCA.…”

Pathological Heterogeneity of Frontotemporal Lobar Degeneration with Ubiquitin-Positive Inclusions Delineated by Ubiquitin Immunohistochemistry and Novel Monoclonal Antibodies

“…Sections were then lightly counterstained with hematoxylin, dehydrated, and coverslipped. Double-labeling immunofluorescence analyses were performed as previously described 24 using Alexa Fluor 488-and 594-conjugated secondary antibodies (Molecular Probes, Eugene, OR) and coverslipped with Vectashield-DAPI mounting medium (Vector Laboratories).…”

New ¿- and ¿-synuclein immunopathological lesions in human brain

“…Findings from several recent studies have suggested that aggregationprone proteins, such as tau, α-syn, polyglutaminecontaining proteins, and amyloid-β, can enhance each other's aggregation [30][31][32][33][34][35]. In particular, β-amyloid augments α-syn accumulation [33,34], Tau increases α-syn aggregation [31,32] while synergistic interactions between β-amyloid, tau, and α-syn might accelerate neuropathology [33]. Importantly, mechanism of hybrid oligomer formation plays an essential role in the pathogenesis of combined AD and PD [30].…”