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Fisahn, A.

Publications and source records attributed to Fisahn, A..

5 recordsLinked to original sources
bioRxiv2025

Microglia Adopt Temporally Specific Subtypes after Irradiation, Correlating with Neuronal Asynchrony

Cranial radiotherapy causes progressive neurocognitive impairments in cancer survivors. Neuroinflammation is a key contributor, but its dynamics and consequences for brain function remain poorly understood. Here, we performed comprehensive longitudinal profiling from 6 hours to 1 year after irradiation (IR) of the mouse hippocampus, using transcriptomic, protein, and histological analyses. We identified delayed microglial responses initiated by mitotic progression coupled interferon signaling. IR rewired the parenchymal phagocyte profiles, triggered by progressive microglial loss, failure of repopulation through self-renewal, and compensatory generation of microglia-like cells derived from peripheral monocytes. These findings were also observed in autopsied human brain. Finally, we demonstrate two phases of neuronal asynchrony, an early one associated with inflammation and a late one associated with aberrant synaptic regulation. These results provide comprehensive, longitudinal insights into microglia responses that can aid in tailoring therapies to preserve cognition in cancer survivors.

neuroscience↗
bioRxiv2024

Association of microglia loss with hippocampal network impairments as a turning point in the amyloid pathology progression.

Alzheimers disease is a progressive neurological disorder causing memory loss and cognitive decline. The underlying causes of cognitive deterioration and neurodegeneration remain unclear, leading to a lack of effective strategies to prevent dementia. Recent evidence highlights the role of neuroinflammation, particularly involving microglia, in Alzheimers disease onset and progression. Characterizing the initial phase of Alzheimers disease can lead to the discovery of new biomarkers and therapeutic targets, facilitating timely interventions for effective treatments. We used the AppNL-G-F knock-in mouse model, which resembles the amyloid pathology and neuroinflammatory characteristics of Alzheimers disease, to investigate the transition from a pre-plaque to an early plaque stage with a combined functional and molecular approach. Our experiments show a progressive decrease in the power of cognition-relevant hippocampal gamma oscillations during the early stage of amyloid pathology, together with a modification of fast-spiking interneuron intrinsic properties and postsynaptic input. Consistently, transcriptomic analyses revealed that these effects are accompanied by changes in synaptic function-associated pathways. Concurrently, homeostasis-and inflammatory-related microglia signature genes were downregulated. Moreover, we found a decrease in Iba1-positive microglia in the hippocampus that correlates with plaque aggregation and neuronal dysfunction. Collectively, these findings support the hypothesis that microglia play a protective role during the early stages of amyloid pathology by preventing plaque aggregation, supporting neuronal homeostasis, and overall preserving the oscillatory networks functionality. These results suggest that the early loss of microglia could be a pivotal event in the progression of Alzheimers disease, potentially triggering plaque deposition, impairment of fast-spiking interneurons, and the breakdown of the oscillatory circuitry in the hippocampus.

neuroscience↗
bioRxiv2022

Signal Peptide Peptidase-Like 2b affects APP cleavage and exhibits a biphasic Aβ-mediated expression in Alzheimer's disease.

Alzheimers disease (AD) is a multifactorial disorder driven by abnormal amyloid {beta}-peptide (A{beta}) levels. To identify new druggable pathways involved in the A{beta} cascade we here investigated the AD pathophysiological role of the presenilin-like intramembrane protease signal peptide peptidase-like 2b (SPPL2b). A{beta}42 induced a biphasic modulation of SPPL2b expression in human cell lines and ex vivo mouse brain slices. In addition, SPPL2b was elevated in AppNL-G-F knock-in AD mice as well as in human AD samples. Early high neuronal expression of SPPL2b was followed by a downregulation in late AD pathology in both AppNL-G-F mice and Braak stage V AD brains. Importantly, SPPL2b overexpression or its genetic deletion significantly increased or reduced APP cleavage and A{beta} production, respectively. Thus, our results strongly support the involvement of SPPL2b in AD pathology. The early A{beta}-induced SPPL2b upregulation may enhance A{beta} production in a vicious cycle further aggravating the A{beta} pathology suggesting SPPL2b as a potential anti-A{beta} drug target.

neuroscience↗
bioRxiv2021

Molecular chaperone ability to inhibit amyloid-derived neurotoxicity, but not amorphous protein aggregation, depends on a conserved pH-sensitive Asp residue

Proteins can self-assemble into amyloid fibrils or amorphous aggregates and thereby cause disease. Molecular chaperones can prevent both these types of protein aggregation, but the respective mechanisms are not fully understood. The BRICHOS domain constitutes a disease-associated small heat shock protein-like chaperone family, with activities against both amyloid toxicity and amorphous protein aggregation. Here, we show that the activity of two BRICHOS domain families against Alzheimers disease associated amyloid-{beta} neurotoxicity to mouse hippocampi in vitro depends on a conserved aspartate residue, while the ability to suppress amorphous protein aggregation is unchanged by Asp to Asn mutations. The conserved Asp in its ionized state promotes structural flexibility of the BRICHOS domain and has a pKa value between pH 6.0-7.0, suggesting that chaperone effects against amyloid toxicity can be affected by physiological pH variations. Finally, the Asp is evolutionarily highly conserved in >3000 analysed BRICHOS domains but is replaced by Asn in some BRICHOS families and animal species, indicating independent evolution of molecular chaperone activities against amyloid fibril formation and non-fibrillar amorphous protein aggregation.

biochemistry↗