Biology subjects

Shakirzyanova, A.

Publications and source records attributed to Shakirzyanova, A..

4 recordsLinked to original sources

bioRxiv2025

Early amyloid spine response and impaired synaptic transmission of pyramidal neurons in human biopsies with Alzheimer's Disease-related pathology

Studies of neuronal functions during the pathological progression of Alzheimers disease (AD) in humans are limited due to the lack of live human brain tissue from patients with AD. To address this gap, we have established an exceptional approach to study the electrophysiological properties and cell morphologies of human neurons in acute slices obtained from cortical biopsies of patients with idiopathic normal pressure hydrocephalus (iNPH). Histological examination of Broadman area 8-9 cortical biopsies from these patients have revealed that approximately 40% of the patients show signs of early AD-related pathology in the form of low to moderate, often fleecy beta-amyloid (A{beta}) deposits and additional, occasional tau in 10% of the cases. Thus, the iNPH brain biopsies, obtained during the shunt surgery to treat the patients, offer a unique window to investigate how existing AD-related pathology alters the operational properties of human cortical neurons. Here we carried out integrative analysis of human neuronal electrophysiology at single neuron and network level followed by subsequent cellular morphological reconstructions to register the primary pathological changes in neuronal functions in correlation with existing AD-related pathology. The presence of A{beta} plaques induced a decrease in basal excitatory synaptic activity in pyramidal neurons residing on supragranular layers of the cortex. These neurons received less of L1-induced inhibition and appeared hyperexcitable in response to application to NMDA in multielectrode array (MEA) recordings. Interestingly, the global spine density of supraganular pyramidal neurons was increased in biopsies with AD-related pathology. The increase in spine density was coincidental with a partial recovery of excitatory transmission (frequency but not amplitude), of L1-induced inhibition in supragranular layers pyramidal neurons and of NMDA induced supragranular firing (but not of bursting hyperexcitability) indicating a potential differential effect of tau in the presence of A{beta} on the progression of neuronal functions. Despite the partial renormalization of deficits seen in cases with A{beta} pathology only, pyramidal neurons in cases with both A{beta} and tau exhibited more consistent deficits in the intrinsic neuronal properties with increase in sodium and potassium currents and a strong propensity to bursting under NMDA stimulation. We conclude that complex mechanisms operate in response to accumulation of A{beta} and tau including re-structuring of the apparatus of synaptic transmission and consolidation of a hyperexcitable supragranular cortical network phenotype. The observed changes in spine density and synaptic activity are reminiscent of parallels seen in homeostatic plasticity and synaptic scaling and may depend on strong interactions with the local microenvironment (astrocytes and microglia). This is the first study to report the impact of AD-related pathology on single-neuron operational properties and morphology in humans.

neuroscience↗

bioRxiv2024

Frontotemporal dementia patient-derived iPSC neurons show cell pathological hallmarks and evidence for synaptic dysfunction and DNA damage

Frontotemporal dementia (FTD) is the second most common cause of dementia in patients under 65 years, characterized by diverse clinical symptoms, neuropathologies, and genetic background. Synaptic dysfunction is suggested to play a major role in FTD pathogenesis. Disturbances in the synaptic function can also be associated with the C9orf72 repeat expansion (C9-HRE), the most common genetic mutation causing FTD. C9-HRE leads to distinct pathological hallmarks, such as C9orf72 haploinsufficiency and development of toxic RNA foci and dipeptide repeat proteins (DPRs). FTD patient brains, including those carrying the C9-HRE, are also characterized by neuropathologies involving accumulation of TDP-43 and p62/SQSTM1 proteins. This study utilized induced pluripotent stem cell (iPSC)-derived cortical neurons from C9-HRE-carrying or sporadic FTD patients and healthy control individuals. We report that the iPSC neurons derived from C9-HRE carriers developed typical C9-HRE-associated hallmarks, including RNA foci and DPR accumulation. All FTD neurons demonstrated increased TDP-43 nucleus-to-cytosolic shuttling and p62/SQSTM1 accumulation, and changes in nuclear size and morphology. In addition, the FTD neurons displayed reduced number and altered morphologies of dendritic spines and significantly altered synaptic function indicated by a decreased response to stimulation with GABA. These structural and functional synaptic disturbances were accompanied by upregulated gene expression in the FTD neurons related to synaptic function, including synaptic signaling, glutamatergic transmission, and pre- and postsynaptic membrane, as compared to control neurons. Pathways involved in DNA repair were significantly downregulated in FTD neurons. Only one gene, NUPR2, potentially involved in DNA damage response, was differentially expressed between the sporadic and C9-HRE-carrying FTD neurons. Our results show that the iPSC neurons from FTD patients recapitulate pathological changes of the FTD brain and strongly support the hypothesis of synaptic dysfunction as a crucial contributor to disease pathogenesis in FTD.

neuroscience↗

bioRxiv2022

Microglial amyloid beta clearance is driven by PIEZO1 channels

BackgroundMicroglia are the endogenous immune cells of the brain and act as sensors of pathology to maintain brain homeostasis and eliminate potential threats. In Alzheimers disease (AD), toxic amyloid beta (A{beta}) accumulates in the brain and forms stiff plaques. In late-onset AD accounting for 95% of all cases, this is thought to be due to reduced clearance of A{beta}. Human genome-wide association studies and animal models suggest that reduced clearance results from aberrant function of microglia. While the impact of neurochemical pathways on microglia have been broadly studied, mechanical receptors regulating microglial functions remain largely unexplored. MethodsHere we showed that a mechanotransduction ion channel, PIEZO1, is expressed and functional in human and mouse microglia. We used a small molecule agonist, Yoda1, to study how activation of PIEZO1 affects AD-related functions in human induced pluripotent stem cell (iPSC) -derived microglia-like cells (iMGL) under controlled laboratory experiments. Cell survival, metabolism, phagocytosis and lysosomal activity were assessed using real-time functional assays. To evaluate the effect of activation of PIEZO1 in vivo, 5-month-old 5xFAD male mice were infused daily with Yoda1 for two weeks through intracranial cannulas. Microglial Iba1 expression and A{beta} pathology were quantified with immunohistochemistry and confocal microscopy. Published human and mouse AD datasets were used for in-depth analysis of PIEZO1 gene expression and related pathways in microglial subpopulations. ResultsWe show that PIEZO1 orchestrates A{beta} clearance by enhancing microglial survival, phagocytosis, and lysosomal activity. A{beta} inhibited PIEZO1-mediated calcium transients, whereas activation of PIEZO1 with a selective agonist, Yoda1, improved microglial phagocytosis resulting in A{beta} clearance both in human and mouse models of AD. Moreover, PIEZO1 expression was associated with a unique microglial transcriptional phenotype in AD as indicated by assessment of cellular metabolism, and human and mouse single cell datasets. ConclusionThese results indicate that the compromised function of microglia in AD could be improved by controlled activation of PIEZO1 channels resulting in alleviated A{beta} burden. Pharmacological regulation of these mechanoreceptors in microglia could represent a novel therapeutic paradigm for AD. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=176 HEIGHT=200 SRC="FIGDIR/small/484831v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@832eadorg.highwire.dtl.DTLVardef@6d8719org.highwire.dtl.DTLVardef@c09740org.highwire.dtl.DTLVardef@9fa85_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Microglia orchestrate neuronal activity in brain organoids

Human stem cell-derived brain organoids provide a physiologically relevant in vitro 3D brain model for studies of neurological development that are unique to the human nervous system. Prior studies have reported protocols that support the maturation of microglia from mesodermal progenitors leading to innately developing microglia within the organoids. However, although microglia are known to support neuronal development in rodents, none of the previous studies have reported what is the impact of microglia on neuronal growth and maturation in human brain organoids. Here we show that incorporating microglial progenitors into the developing organoid supports neuronal maturation, the emergence of neurons capable of firing repetitive action potentials and the appearance of synaptic and neuronal bursting activity. Immunocompetent organoids enable experimental strategies for interrogating fundamental questions on microglial and neuronal diversity and function during human brain development.

neuroscience↗