Biology subjects

Granholm, A.-C.

Publications and source records attributed to Granholm, A.-C..

3 recordsLinked to original sources

bioRxiv2025

Polyamine biosynthesis dysregulation in Alzheimer's disease and Down syndrome cellular models

BACKGROUNDIndividuals with Down Syndrome (DS) frequently develop early onset Alzheimers disease (AD) with pathological hallmarks closely resembling AD due to several triplicated genes on chromosome 21. Polyamines are small, organic molecules that play a pivotal role for growth and differentiation, and a dysregulation of polyamine pathways is implicated in AD pathology. However, their role in DS-associated AD is unclear. METHODSWe analyzed polyamines and their metabolite levels in mouse hippocampal cells and human DS-AD and AD hippocampal tissue and assessed the effects of the ODC inhibitor difluoromethylornithine (DFMO) on A{beta}42 aggregation and protein expression in DS fibroblasts. RESULTSAmyloid-{beta}42 increased polyamine levels via ornithine decarboxylase (ODC) activation in a dose-dependent manner. DFMO reduced A{beta}42 aggregation, decreased amyloid precursor protein (APP) levels, and normalized proteins linked to AD pathology in DS fibroblasts. Polyamine levels were elevated in DS-AD hippocampal tissue, with colocalization of ODC and A{beta}42 aggregates. CONCLUSIONThese findings suggest that polyamine biosynthesis may exacerbate A{beta}42 toxicity and APP expression, contributing to AD progression in DS. The ability of DFMO to reduce A{beta}42 aggregation and restore protein homeostasis presents the polyamine pathway as a therapeutic target for DS-AD management.

biochemistry↗

bioRxiv2023

A New Role for RNA G-quadruplexes in Aging and Alzheimer's Disease

INTRODUCTIONAs the world population ages, new molecular targets in aging and Alzheimers Disease (AD) are needed to combat the expected influx of new AD cases. Until now, the role of RNA structure in aging and neurodegeneration has largely remained unexplored. METHODSIn this study, we examined human hippocampal postmortem tissue for the formation of RNA G-quadruplexes (rG4s) in aging and AD. RESULTSWe found that rG4 immunostaining strongly increased in the hippocampus with both age and with AD severity. We further found that neurons with accumulation of phospho-tau immunostaining contained rG4s, that rG4 structure can drive tau aggregation, and that rG4 staining density depended on APOE genotype in the human tissue examined. DISCUSSIONCombined with previous studies showing the dependence of rG4 structure on stress and the extreme power of rG4s at oligomerizing proteins, we propose a model of neurodegeneration in which chronic rG4 formation is linked to proteostasis collapse. These morphological findings suggest that further investigation of RNA structure in neurodegeneration is a critical avenue for future treatments and diagnoses.

neuroscience↗

bioRxiv2020

Distinctive alteration of presynaptic proteins in the outer molecular layer of the dentate gyrus in Alzheimer's disease

Synaptic degeneration has been reported as one of the best pathological correlate of cognitive deficit in Alzheimers Disease (AD). However, the location of these synaptic alterations within hippocampal sub-regions, the vulnerability of the presynaptic versus postsynaptic compartments, and the biological mechanisms for these impairments remain unknown. Here, we performed immunofluorescence labeling of different synaptic proteins in fixed and paraffin embedded human hippocampal sections and report reduced levels of several presynaptic proteins of the neurotransmitter release machinery (complexin-1, syntaxin-1A, synaptotagmin-1 and synaptogyrin-1) in AD cases. The deficit was restricted to the outer molecular layer (OML) of the dentate gyrus whereas other hippocampal sub-fields were preserved. Interestingly, standard markers of postsynaptic densities (SHANK2) and dendrites (MAP2) were unaltered, as well as the relative number of granule cells in the dentate gyrus, indicating that the deficit is preferentially presynaptic. Notably, staining for the axonal components, myelin basic protein, SMI-312 and Tau, was unaffected, suggesting that the local presynaptic impairment does not result from axonal loss or alterations of structural proteins of axons. There was no correlation between the reduction in presynaptic proteins in OML and the extent of the amyloid load or of the dystrophic neurites expressing phosphorylated forms of Tau. Altogether, this study highlights the distinctive vulnerability of the OML of dentate gyrus and supports the notion of presynaptic failure in AD.

neuroscience↗