Biology subjects

Middeldorp, J.

Publications and source records attributed to Middeldorp, J..

3 recordsLinked to original sources

bioRxiv2021

Transcriptomic and functional analysis of Aβ1-42 oligomer-stimulated human monocyte-derived microglia-like cells

Dysregulation of microglial function contributes to Alzheimers disease (AD) pathogenesis. Several genetic and transcriptome studies have revealed microglia specific genetic risk factors, and changes in microglia expression profiles in AD pathogenesis, viz. the human-Alzheimers microglia/myeloid (HAM) profile in AD patients and the disease-associated microglia profile (DAM) in AD mouse models. The transcriptional changes involve genes in immune and inflammatory pathways, and in pathways associated with A{beta} clearance. A{beta} oligomers have been suggested to be the initial trigger of microglia activation in AD. To study the direct response to A{beta} oligomers exposure, we assessed changes in gene expression in an in vitro model for microglia, the human monocyte-derived microglial-like (MDMi) cells. We confirmed the initiation of an inflammatory profile following LPS stimulation, based on increased expression of IL1B, IL6, and TNF. In contrast, the A{beta}1-42 oligomers did not induce an inflammatory profile or a classical HAM or DAM profile. Interestingly, we observed a specific increase in the expression of metallothioneins in the A{beta}1-42 oligomer treated MDMi cells. Metallothioneins are involved in metal ion regulation, protection against reactive oxygen species, and have anti-inflammatory properties. In conclusion, our data suggests that A{beta}1-42 oligomers may trigger a protective response both in vitro and in vivo.

neuroscience↗

bioRxiv2021

Loss of lamin-B1 and defective nuclear morphology are hallmarks of astrocyte senescence in vitro and in the aging human hippocampus

The increase in senescent cells in tissues, including the brain, is a general feature of normal aging and age-related pathologies. Senescent cells exhibit a specific phenotype, which includes an altered nuclear morphology and transcriptomic changes. Astrocytes undergo senescence in vitro and in age-associated neurodegenerative diseases, but little is known about whether this process also occurs in physiological aging. Here, we investigated astrocyte senescence in vitro, in old mouse brains and in post-mortem human brain tissue of elderly. We identified a significant loss of lamin-B1, a major component of the nuclear lamina, as a hallmark of senescent astrocytes. We showed a severe reduction of lamin-B1 in the dentate gyrus of aged mice, including in hippocampal astrocytes, and in the granular cell layer of the hippocampus of post-mortem human tissue from non-demented elderly. Interestingly, the lamin-B1 reduction was associated with nuclear deformations, represented by an increased incidence of invaginated nuclei and loss of nuclear circularity in senescent astrocytes in vitro and in the aging human hippocampus. In conclusion, our findings show that reduction of lamin-B1 is a conserved hallmark of astrocyte aging, as well as shed light on significant defects in nuclear lamina structure, which may impact astrocyte function during human aging.

neuroscience↗

bioRxiv2021

SARS-CoV-2 causes brain inflammation and induces Lewy body formation in macaques

SARS-CoV-2 may cause acute respiratory disease, but the infection can also initiate neurological symptoms. Here we show that SARS-CoV-2 infection causes brain inflammation in the macaque model. An increased metabolic activity in the pituitary gland of two macaques was observed by longitudinal positron emission tomography-computed tomography (PET-CT). Post-mortem analysis demonstrated infiltration of T-cells and activated microglia in the brain, and viral RNA was detected in brain tissues from one animal. We observed Lewy bodies in brains of all rhesus macaques. These data emphasize the virus capability to induce neuropathology in this nonhuman primate model for SARS-CoV-2 infection. As in humans, Lewy body formation is an indication for the development of Parkinsons disease, this data represents a warning for potential long-term neurological effects after SARS-CoV-2 infection. TeaserSARS-CoV-2 causes brain inflammation and Lewy bodies, a hallmark for Parkinson, after an asymptomatic infection in macaques.

neuroscience↗