Biology subjects

Netherlands Brain Bank,

Publications and source records attributed to Netherlands Brain Bank,.

3 recordsLinked to original sources

bioRxiv2026

Disease-specific tangle immunophenotypes distinguish hippocampal vulnerability in Alzheimers disease and Parkinsons disease dementia

Structured AbstractINTRODUCTION Tau pathology typically occurs in Alzheime[r]s disease (AD), however is also frequently present in Parkinso[n]s disease dementia (PDD) and Dementia with Lewy Bodies (DLB), yet its disease-specific signature is unclear. METHODSFive tau, amyloid-{beta}, -synuclein and neuronal markers were analysed across hippocampal subfields in non-demented controls (CTLs), AD, PDD and DLB using multiplex immunohistochemistry, single-tangle classification and confocal imaging. RESULTSAT8, pTau217, and GT38 were predominatly detected in AD, while pS422 was enriched in PDD and pS396 showed a region- and disease-specific pattern. DLB resembled AD in subregional tau distribution. Tau marker correlation were different comparing AD, PDD and CTL. Single-tangle analyses revealed disease-specific immunophenotypes but conserved mature intra-tangle epitope organisation. Distinct tau signatures were associated with inhibitory interneuron vulnerability, while regional tau co-occurrence with amyloid-{beta} and -synuclein remained conserved. DISCUSSIONDisease-specific tau signatures vary across hippocampal subregions and neuronal populations, implicating the contribution of regional and cell-specific factors beyond pathology burden.

neuroscience↗

bioRxiv2025

GPC5 expression highlights astrocytic heterogeneity and divergent hippocampal responses in Alzheimer's and Parkinson's Dementia

Regional heterogeneity of astrocytes and neurons is increasingly recognised as a determinant of selective vulnerability in neurodegeneration, yet the molecular signatures underlying this specificity remain poorly defined. Glypican-5 (GPC5), a heparan sulfate proteoglycan expressed mainly by astrocytes, contributes to synaptic organisation and circuit stability, whose disruption may undermine astrocyte-neuron crosstalk and contribute to selective neuronal loss in neurodegenerative diseases. Using multiplex chromogenic immunohistochemistry, in situ hybridization and digital pathology, we mapped GPC5 expression across the hippocampus and parahippocampal cortex in post-mortem tissue from non-demented control (CTL), Alzheimers disease (AD) and Parkinsons disease with dementia (PDD) cases. In CTL brains, GPC5 labelled spatially restricted populations of astrocytes and pyramidal neurons organized according to hippocampal subfield and laminar architecture. GPC5-positive astrocytes co-expressed canonical markers but represented a more restricted population while GPC5 protein was enriched at synapse-rich regions of the outer molecular layer of the dentate gyrus. In AD and PDD, regional distribution patterns of GPC5 were distinct from canonical astrocyte markers including GFAP, AQP4 and ALDH1L1. In PDD, GPC5 distribution was largely preserved. In AD, GPC5 underwent selective redistribution with a significant loss of the staining in the dentate gyrus, and an accumulation on amyloid plaques, putatively secreted by plaque-associated astrocytes, and on neurofibrillary tangles, likely of neuronal and astrocytic origin These findings reveal disease- and region-specific remodelling of a spatially organised astrocyte-neuron system and establish GPC5 as a molecularly distinct responder to AD pathology.

neuroscience↗

bioRxiv2024

A microglia clonal inflammatory disorder in Alzheimer's Disease

Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however few studies have investigated its role in neurodegenerative processes such as Alzheimers Disease (AD). Here we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in human, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients. One-Sentence SummaryA subset of Alzheimer Disease patients carry mutant microglia somatic clones which promote neuro-inflammation.

neuroscience↗