Biology subjects

Leary, N.

Publications and source records attributed to Leary, N..

4 recordsLinked to original sources

bioRxiv2025

Cellular and Regional Vulnerability Shapes the Molecular Landscape of Psychosis in Alzheimers Disease

Approximately 40 percent of Alzheimers disease patients develop psychosis (AD+P), yet the molecular and cellular basis of these symptoms remains poorly understood. Here we profiled single-nucleus transcriptomes and epigenomes from 48 postmortem Alzheimers brains stratified by psychiatric diagnosis. Across cell types, AD+P was distinguished by transcriptional programs in upper-layer cortical pyramidal neurons consistent with re-engagement of developmental and structural plasticity pathways. These neurons exhibited greater loss in AD+P cortex, indicating that such programs emerge in a context of heightened vulnerability. Integrating these findings with functional perturbation screens in stem-cell-derived brain organoids, we found that activation of these programs alters cortico-cortical network connectivity and can exacerbate network dysfunction. Our data suggest that compensatory neuronal plasticity, shaped by glial inflammatory responses, may paradoxically contribute to circuit instability and selective vulnerability underlying neuropsychiatric symptoms in dementia. HighlightsO_LICell-type- and brain-region-specific transcriptional changes in AD with psychosis (AD+P) C_LIO_LIUpper-layer pyramidal dysfunction and metabolic vulnerability marks the pathophysiology of AD+P C_LIO_LICircuit wiring programs are evoked in AD+P as maladaptive compensatory responses C_LIO_LIAD+P-associated IL-6 signaling impairs neuronal network function in brain organoids C_LI

neuroscience↗

bioRxiv2024

An aging-sensitive compensatory secretory phospholipase that confers neuroprotection and cognitive resilience

Breakdown of lipid homeostasis is thought to contribute to pathological aging, the largest risk factor for neurodegenerative disorders such as Alzheimers Disease (AD). Cognitive reserve theory posits a role for compensatory mechanisms in the aging brain in preserving neuronal circuit functions, staving off cognitive decline, and mitigating risk for AD. However, the identities of such mechanisms have remained elusive. A screen for hippocampal dentate granule cell (DGC) synapse loss-induced factors identified a secreted phospholipase, Pla2g2f, whose expression increases in DGCs during aging. Pla2g2f deletion in DGCs exacerbates aging-associated pathophysiological changes including synapse loss, inflammatory microglia, reactive astrogliosis, impaired neurogenesis, lipid dysregulation and hippocampal-dependent memory loss. Conversely, boosting Pla2g2f in DGCs during aging is sufficient to preserve synapses, reduce inflammatory microglia and reactive gliosis, prevent hippocampal-dependent memory impairment and modify trajectory of cognitive decline. Ex vivo, neuronal-PLA2G2F mediates intercellular signaling to decrease lipid droplet burden in microglia. Boosting Pla2g2f expression in DGCs of an aging-sensitive AD model reduces amyloid load and improves memory. Our findings implicate PLA2G2F as a compensatory neuroprotective factor that maintains lipid homeostasis to counteract aging-associated cognitive decline.

neuroscience↗

bioRxiv2023

A single-cell atlas of ABCA7 loss-of-function reveals lipid disruptions, mitochondrial dysfunction and DNA damage in neurons

Loss-of-function (LoF) variants in the lipid transporter ABCA7 significantly increase Alzheimers disease risk (odds ratio {approx} 2), yet the underlying pathogenic mechanisms and specific neural cell types affected remain unclear. To investigate this, we generated a single-nucleus RNA sequencing atlas of 36 human postmortem prefrontal cortex samples, including 12 carriers of ABCA7 LoF variants and 24 matched non-carriers. ABCA7 LoF variants were associated with transcriptional changes across all major neural cell types. Excitatory neurons, which expressed the highest levels of ABCA7, showed significant alterations in oxidative phosphorylation, lipid metabolism, DNA damage responses, and synaptic signaling pathways. ABCA7 LoF-associated transcriptional changes in neurons were similarly perturbed in carriers of the common AD missense variant ABCA7 p.Ala1527Gly (n = 240 controls, 135 carriers) predicted by molecular dynamic simulations to disrupt ABCA7 structure -, indicating that findings from our study may extend to large portions of the at-risk population. Human induced pluripotent stem cell (iPSC)-derived neurons carrying ABCA7 LoF variants closely recapitulated the transcriptional changes observed in human postmortem neurons. Biochemical experiments further demonstrated that ABCA7 LoF disrupts mitochondrial membrane potential via regulated uncoupling, increases oxidative stress, and alters phospholipid homeostasis in neurons, notably elevating saturated phosphatidylcholine levels. Supplementation with CDP-choline to enhance de novo phosphatidylcholine synthesis effectively reversed these transcriptional changes, restored mitochondrial uncoupling, and reduced oxidative stress. Additionally, CDP-choline normalized amyloid-{beta} secretion and alleviated neuronal hyperexcitability in ABCA7 LoF neurons. This study provides a detailed transcriptomic profile of ABCA7 LoF-induced changes and highlights phosphatidylcholine metabolism as a key driver in ABCA7-induced risk. Our findings suggest a promising therapeutic approach that may benefit a large proportion of individuals at increased risk for Alzheimers disease.

neuroscience↗

bioRxiv2022

Lipid Accumulation Induced by APOE4 Impairs Microglial Surveillance of Neuronal-Network Activity

Apolipoprotein E4 (APOE4) is the greatest known genetic risk factor for developing late- onset Alzheimers disease and its expression in microglia is associated with pro- inflammatory states. How the interaction of APOE4 microglia with neurons differs from microglia expressing the disease-neutral allele APOE3 is currently unknown. Here, we employ CRISPR-edited induced pluripotent stem cells (iPSCs) to dissect the impact of APOE4 in neuron-microglia communication. Our results reveal that APOE4 induces a distinct metabolic program in microglia that is marked by the accumulation of intracellular neutral lipid stores through impaired lipid catabolism. Importantly, this altered lipid-accumulated state shifts microglia away from homeostatic surveillance and renders APOE4 microglia weakly responsive to neuronal activity. By examining the transcriptional signatures of APOE3 versus APOE4 microglia before and after exposure to neuronal conditioned media, we further established that neuronal soluble cues differentially induce a lipogenic program in APOE4 microglia that exacerbates pro- inflammatory signals. Pharmacological blockade of lipogenesis in APOE4 microglia is sufficient to diminish intracellular lipid accumulation and restore microglial homeostasis. Remarkably, unlike APOE3 microglia that support neuronal network activity, co-culture of APOE4 microglia with neurons disrupts the coordinated activity of neuronal ensembles. We identified that through decreased uptake of extracellular fatty acids and lipoproteins, APOE4 microglia disrupts the net flux of lipids which results in decreased neuronal activity via the potentiation of the lipid-gated K+ channel, GIRK3. These findings suggest that neurological diseases that exhibit abnormal neuronal network-level disturbances may in part be triggered by impairment in lipid homeostasis in non-neuronal cells, underscoring a novel therapeutic route to restore circuit function in the diseased brain. O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/484146v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@4d4a9corg.highwire.dtl.DTLVardef@5d888corg.highwire.dtl.DTLVardef@afa191org.highwire.dtl.DTLVardef@984340_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗