Biology subjects

Mitrecic, D.

Publications and source records attributed to Mitrecic, D..

3 recordsLinked to original sources

bioRxiv2026

Abnormal neuronal and synaptic morphology in Down syndrome brains reproduces in 2D and 3D human cellular models

Down syndrome (DS) is the most common autosomal aneuploidy compatible with postnatal survival and is caused by full or partial trisomy of chromosome 21. In this study, human isogenic induced pluripotent stem cells (iPSCs) were differentiated into 2D neurons and cortico-striatal assembloids (hCSAs). Abnormal neuronal morphology was observed: trisomic (T21) neurons formed aggregates of cell bodies interconnected with thick neurite bundles radiating outwards, connected and overlapped with other neurons in between the bundles while disomic (D21) neurons were evenly distributed across the surface and formed strong neuronal networks. Detailed analysis revealed significantly shorter neurites with larger diameter, fewer branches, and fewer terminal points in T21 neurons compared to D21 neurons in both 2D cultures and hCSAs. We observed similar phenotypes in foetal and postnatal human brain tissue. Furthermore, we observed abnormal mitochondrial morphology with an excess of some mitochondrial proteins (AIF, TOMM20), abnormal synaptic morphology and significantly lower expression of both presynaptic and postsynaptic markers (SYN-1, PSD95 and GEPH) throughout in vitro differentiation of T21 neurons. Finally, our data showed that T21 spheroids were significantly smaller throughout in vitro differentiation compared to D21 spheroids. T21 spheroids also exhibited significantly higher expression of neural stem cells (SOX2), significantly lower expression of proliferating cells (Ki67) and significantly higher expression of apoptotic cells (CCaspase-3). Overall, our study demonstrates that T21 leads to abnormal neuronal morphology in both 2D neurons and hCSAs, consistent with observations in the human brain.

neuroscience↗

bioRxiv2020

Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene-dose-sensitive AD-suppressor in human brain

A population of >6 million people worldwide at high risk of Alzheimers disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of {beta}-amyloid-(A{beta})-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar A{beta} deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome-21-gene BACE2, but prevented by combined chemical {beta} and {gamma}-secretase inhibition. We found that T21-organoids secrete increased proportions of A{beta}-preventing (A{beta}1-19) and A{beta}-degradation products (A{beta}1-20 and A{beta}1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1-inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in [~]30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.

neuroscience↗

bioRxiv2019

The Innate Immune Toll-Like Receptor-2 modulates the Depressogenic and Anorexiolytic Neuroinflammatory Response in Obstructive Sleep Apnoea

BackgroundThe neurological mechanisms of the disease process of obstructive sleep apnea, the second most frequent sleep disorder, remain unclear whilst its links with several major neuropsychiatric disorders, such as depression, anxiety and even Alzheimers disorder, are increasingly recognised. A radical theory, that inflammation in the brain may underlie certain phenotypes of many of these disorders, has been proposed, and the microglial TLR2 system may serve as an important crossroad at the borderlands of several pathogenesis. This study undertook to investigate whether a neuroinflammatory response occurs under conditions of OSA, and whether it might be related to a modulated response due to TLR2 functionality in an established rodent model of OSA. MethodsThe effects of three weeks exposure to chronic intermittent hypoxia were monitored in mice with or without functional TLR2 (C57BL/6-Tyrc-Brd-Tg(Tlr2-luc/gfp)Kri/Gaj; TLR2-/-, C57BL/6-Tlr2tm1Kir), that were investigated by multimodal in vivo and ex vivo imaging, combining magnetic resonance and bioluminescence imaging and a variety of functional tests. ResultsAn acute neuroinflammatory response was demonstrated following the three days in the basal forebrain of mice, and more chronically in other parts of the frontal cortex. Adaptive changes in specific neurocircuitry were demonstrated, with significant links to agitated (mal)adaptive behaviour under episodes of stress, and an increased ability to gain weight. ConclusionsOur results suggest that microglial activation and an innate immune response might be the missing link underlying the pathogenesis of well known structural, psychologic and metabolic changes experienced by some patients with OSA.

neuroscience↗