Biology subjects

Swaab, D. F.

Publications and source records attributed to Swaab, D. F..

5 recordsLinked to original sources

bioRxiv2025

Reduced triacylglycerols and lipid droplets are associated with resilience to Alzheimers disease

IntroductionWhile it has become clear that alterations in lipid metabolism are associated with AD, it is unclear how they contribute to both cognitive decline and the pathophysiology of AD. MethodsWe performed lipidomics and activity-based protein profiling in the frontal cortex of control, AD and resilient donors, i.e. individuals with AD pathology without cognitive decline. Subsequently we integrated these data using multi-omics factor analysis and correlated the multi-omics profiles to disease and clinical parameters. ResultsThe most pronounced alterations in lipids were in the {omega}6-derived oxylipins, which were particularly increased in the AD patients. Both triacylglycerols (TAGs) and lipid droplets were more abundant in the AD donors compared to the resilient donors. Enzyme activities showed a similar direction in the AD and resilient donors, including decreased activity of ABHD6. Multi-omics factor analysis showed that increased oxylipins, loss of inhibitory cells, synaptic genes and genes related to the inflammatory response were associated with A{beta} plaque load in both AD and resilient donors. ConclusionOur multi-omics data show a response associated with A{beta} load shared among AD and resilient donors and, for the first time, reduced lipid droplets in resilient donors.

neuroscience↗

bioRxiv2025

Neuropathological changes in the nucleus basalis of Meynert in people with type 1 or type 2 diabetes mellitus.

People with type 1 or type 2 diabetes mellitus (T1DM or T2DM) often experience cognitive impairment. We profiled cells in the nucleus basalis of Meynert (NBM) in postmortem human brain tissues to investigate neuropathological changes. 71 postmortem NBM samples were grouped by T1DM, T2DM and non-diabetic controls, with Braak stage 0-2 or 3-6. T1DM subjects had only Braak stage 0-2 and were thus compared only to controls with a similar Braak stage and not subjects with Braak stage 3-6. We analysed neurons expressing choline acetyltransferase (ChAT), phosphorylated-Tau, glial cells and vasculature with respective markers. We found significantly less neuronal expression of ChAT in T1DM compared to controls and T2DM with Braak stage 0-2. Later-stage hyperphosphorylated-Tau levels were higher in T2DM compared to controls with Braak stages 3-6. Our results suggest that reduced acetylcholine production by NBM neurons might underlie the cognitive complains of people with T1DM. In contrast, T2DM may exacerbate neuropathological changes associated with Alzheimers disease-like alterations.

neuroscience↗

bioRxiv2022

Stress-associated purinergic receptors code for fatal suicidality in the hippocampal-hypothalamic-prefrontal circuit

Imbalanced purine metabolism is a key neurological basis for suicide and mood disorders (MD), wherein purinergic receptors in stress-sensitive cerebral regions are thought to be differentially activated. A hippocampal network that links the hypothalamus and prefrontal cortex implements an affective sensation of stress. We discovered that the hippocampus encoded fatal suicidal ideations in the dentate gyrus (DG) by a considerable amount of the granule cell nuclei with P2X purinoceptor 7 (P2RX7) expression, irrespective of the underlying MD. Compared to controls, patients with MD showed microglial dyshomeostasis throughout the hippocampal formation. Strikingly, P2Y purinoceptor 12 (P2RY12)-expressing microglia with segmented processes were remarkably present in the superficial layers of the medial entorhinal cortex (mEnt) in individuals with fatal suicidality. In the hypothalamic stress-sensitive nuclei, P2RY12+ microglia were more expressed in the supraoptic nucleus in MD and even higher when fatal suicidality was present. In the prefrontal cortex, P2RX7 transcripts sharply dropped in suicidal individuals, possibly removing the prefrontal inhibition of the hippocampus and hypothalamus. Confounder analysis showed that the suicide-specific molecular features faded when the postmortem delay was prolonged. Our findings imply that fatal suicidality presents with unique neuropathological alterations. The DG and mEnt are two crucial areas for deciphering the suicidal consequences. By including brain samples from legal euthanasia donors, suicide-specific biosignatures can be maximally retained. Decoding the bioactive framework through key genes, brain regions and neurological processes involved in suicide neuropathology may provide novel therapeutic strategies for suicidal individuals who are beyond the reach of mental health care.

neuroscience↗

bioRxiv2021

The photobiology of the human circadian clock

In modern society, the widespread use of artificial light at night disrupts the suprachiasmatic nucleus (SCN), which serves as our central circadian clock. Existing models describe excitatory responses of the SCN to primarily blue light, but direct measures in humans are absent. The combination of state-of-the-art neuroimaging techniques and custom-made MRI compatible LED devices allowed to directly measure the light response of the SCN. In contrast to the general expectation, we found that SCN activity was suppressed by light. The suppressions were observed not only in response to narrowband blue light ({lambda}max: 470nm) but remarkably, also in response to green ({lambda}max: 515nm) and orange ({lambda}max: 590nm), but not to violet light ({lambda}max: 405nm). The broadband sensitivity of the SCN implies that strategies on light exposure should be revised: enhancement of light levels during daytime is possible with wavelengths other than blue, while during nighttime, all colors are potentially disruptive.

neuroscience↗

bioRxiv2019

Corticotropin-Releasing Hormone Signaling in the Oval Bed Nucleus of the Stria Terminalis Mediates Chronic Stress-Induced Negative Valence Behaviors Associated with Anxiety

The bed nucleus of stria terminalis (BNST) is a forebrain region highly sensitive to stress that expresses corticotropin-releasing hormone (CRH) neuropeptide at high levels and regulates negative valence behaviors associated with anxiety. However, how chronic stress modulates CRH signaling and neuronal activity in BNST remains unknown. We subjected C57BL6/J mice to a 6-week chronic variable mild stress (CVMS) paradigm and investigated the effects on behavior, BNST cellular neurophysiology, and BNST CRH signaling. We also utilized pharmacological infusions and optogenetics to decipher and mimic the effects of CVMS on BNST cellular neurophysiology and behavior. CVMS elevated plasma corticosterone levels, induced negative valence behaviors associated with anxiety, diminished M-currents (voltage-gated K+ currents that stabilize membrane potential and regulate neuronal excitability), and increased mEPSC amplitude in ovBNST. Additionally, the number of c-fos+, CRH+, and CRH activator pituitary adenylate cyclase-activating polypeptide (PACAP)+ cells were increased while CRH inhibitor striatal-enriched protein tyrosine phosphatase (STEP)+ cells were decreased in ovBNST. These expression data were confirmed with qPCR. CVMS also activated PKA in BNST and the electrophysiological and behavioral effects of CVMS were reversed by ovBNST infusion of the PKA-selective antagonist H89. Moreover, optogenetic activation of ovBNST directly induced negative valence behaviors associated with anxiety, mimicking the effects of CVMS. CVMS mediates effects on negative valence behaviors associated with anxiety by activating CRH signaling components and cellular excitability in ovBNST Our findings decipher an important CRH-associated stress molecular signature in BNST and advance our understanding of the neural circuitry underlying stress-induced disorders.

neuroscience↗