Biology subjects

Geut, H.

Publications and source records attributed to Geut, H..

2 recordsLinked to original sources

bioRxiv2024

Alzheimer's disease copathology in dementia with Lewy bodies is associated with astroglial α-synucleinopathy

BackgroundIn dementia with Lewy bodies (DLB), co-existence of Alzheimers disease (AD) pathology, i.e. amyloid-{beta} plaques and tau tangles, has been associated with a more rapid disease progression. In post-mortem DLB brains, we examined the association between AD copathology and regional load and morphology of -synuclein pathology. Also, we compared regional load and morphology of AD copathology in DLB to pathology in AD. MethodsWe included 50 autopsy-confirmed DLB donors with a clinical DLB phenotype, categorized as having no/low levels of AD copathology (pure DLB, n = 15), or intermediate/high levels of AD copathology (mixed DLB+AD, n = 35), and autopsy-confirmed pure AD donors (n = 14) without - synuclein pathology. We used percentage area of immunopositivity for quantitative assessment of pathology load, and visual scores for semi-quantitative assessment of different morphologies of - synuclein, amyloid-{beta} and phosphorylated tau (p-tau) pathology in fifteen neocortical, limbic and brainstem regions. ResultsMixed DLB+AD compared to pure DLB showed a shorter disease duration (6 {+/-} 3 versus 8 {+/-} 3 years, p = 0.021) and higher frequency of APOE-{varepsilon}4 alleles. A-synuclein load was higher in neocortical regions (temporal, parietal and occipital), but not in brainstem and limbic regions, which was based upon an increase of Lewy bodies, -synuclein-positive astrocytes and -synuclein-positive plaques in these regions. A-synuclein load was most strongly correlated to amyloid-{beta} and p-tau load in temporal (r = 0.38 and r = 0.50 respectively) and occipital regions (r = 0.43 and r = 0.42 respectively). Compared to pure AD, mixed DLB+AD showed a lower amyloid-{beta} load in temporal cortex, CA3 and CA4 region, and lower p-tau loads in frontal and parietal cortex, based both upon presence of fewer neuritic plaques as well as neurofibrillary tangles. ConclusionsIn DLB brains, AD copathology was associated with more neocortical -synuclein pathology, consisting not only of Lewy bodies and plaques, but also of astroglial -synuclein. AD pathology in DLB cases is less than in AD cases, reflecting less advanced pathological stages. Astroglial -synuclein and its relation with AD copathology in DLB should be further studied, as this may play a role in accelerating clinical decline.

pathology↗

bioRxiv2023

Altered TFEB subcellular localization in nigral dopaminergic neurons of subjects with prodromal, sporadic and GBA-related Parkinson's disease and Dementia with Lewy bodies

Transcription factor EB is a master regulator of genes involved in the maintenance of autophagic and lysosomal homeostasis, processes which have been implicated in the pathogenesis of GBA-related and sporadic Parkinsons disease (PD) and dementia with Lewy bodies (DLB). TFEB activation at the lysosomal level results in its translocation from the cytosol to the nucleus. Here, we aimed at investigating whether TFEB subcellular localization is altered in post-mortem human brain of aged individuals with either prodromal PD/DLB (incidental Lewy body disease, iLBD, N=3), GBA-related PD/DLB (N=9) or sPD/DLB (N=9), compared to control subjects (N=12). We scanned nigral dopaminergic neurons using high-resolution confocal and stimulated emission depletion (STED) microscopy and semi-quantitatively scored the observed TFEB subcellular localization patterns. In line with previous studies, we observed reduced nuclear TFEB immunoreactivity in PD/DLB patients compared to controls, both sporadic and GBA-related cases, as well as in iLBD cases. Nuclear depletion of TFEB was more pronounced in neurons with Ser129-phosphorylated (pSer129) aSyn cytopathology and in cases carrying pathogenic GBA variants. Interestingly, we further observed previously unidentified TFEB-immunopositive somatic clusters in human brain dopaminergic neurons and in human embryonic stem cell (hESC)-derived neurons, which localized at the Golgi apparatus. The TFEB clustering was more frequently observed and more severe in iLBD, sPD/DLB and GBA-PD/DLB compared to controls, particularly in pSer129 aSyn-positive neurons but also in neurons without apparent cytopathology. Notably, increased frequency of cytoplasmic TFEB clusters in aSyn-negative cells correlated with reduced total GBA enzymatic activity and higher Braak LB stage. In the studied patient population, altered TFEB distribution was accompanied by a reduction in overall mRNA expression levels of selected CLEAR genes, indicating a possible early dysfunction of lysosomal regulation. Overall, these findings suggest the early cytoplasmic TFEB retention and accumulation at the Golgi prior pSer129 aSyn accumulation in incidental, GBA-related and sporadic PD/DLB and indicate TFEB as potential as early therapeutic target for synucleinopathies

neuroscience↗