Biology subjects

Chial, H. J.

Publications and source records attributed to Chial, H. J..

6 recordsLinked to original sources

bioRxiv2026

Imipramine binds to amyloid-β and extends the survival of Alzheimer's disease patients

Background Apolipoprotein E (apoE) plays numerous roles in the pathogenic pathway to Alzheimer's disease (AD). We previously performed a high-throughput screen and identified the antidepressant imipramine as an inhibitor of the interaction between apoE and amyloid-{beta} (A{beta}). We also found that imipramine use to treat depression in AD patients was associated with better Mini-Mental State Exam (MMSE) scores. Here we studied the mechanisms by which imipramine inhibits the AD pathogenic pathway and investigated its effect on mortality in AD patients. Methods Nuclear magnetic resonance spectroscopy was used to characterize the interaction between imipramine and A{beta} monomers. Human induced pluripotent stem cell (hiPSC)-derived AD cerebral organoids (COs) and transgenic AD rats treated with imipramine underwent neuropathological evaluation, while rat learning and memory were assessed in the Morris Water Maze. AD patient mortality in the National Alzheimer's Coordinating Center's database was analyzed by Kaplan-Meier and Cox proportional hazards models. Results Imipramine inhibits the apoE-A{beta} interaction by binding directly to A{beta} monomers. Imipramine reduces A{beta} accumulation and neuronal cell loss in AD COs. Imipramine-treated female AD rats had enhanced reference memory and increased hippocampal cellularity and cholinergic neurotransmission. AD patients prescribed imipramine had reduced all-cause mortality over 10 years relative to those prescribed other tricyclic antidepressants (TCA), non-TCA antidepressants, or no antidepressants. Conclusions The findings support the conclusions that: a) the mechanism by which apoE confers risk for AD is by catalyzing the polymerization of A{beta} into neurotoxic species, b) targeting apoE is a promising, underappreciated strategy for the prevention of AD, c) imipramine should be used more frequently to treat depression in AD clinical practice, and d) imipramine should be evaluated in prospective trials, particularly in APOE4 carriers, as a potential method to improve cognition and reduce mortality in AD.

neuroscience↗

bioRxiv2026

High-content imaging of live microglia-containing Alzheimer's disease brain organoids

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease for which there is currently no safe and effective treatment. AD is characterized by the pathological aggregation of amyloid-{beta} (A{beta}) in the brain resulting in neuronal dysfunction/death and cognitive decline. Modeling these processes in vitro remains challenging due to the lack of an immune-competent 3D in vitro human model of AD amenable to high-throughput analyses. Conventional cerebral organoids (COs) lack microglia and are optically dense which precludes real-time longitudinal analyses. Here, we employ the fluorescent amyloid probe PyrPeg to selectively monitor A{beta} aggregation, and calcein AM and propidium iodide to assess cellular viability within microglia-containing COs (MCOs). We identify age-dependent DS-AD-associated phenotypes within T21 MCOs including A{beta} neuropathology, neurodegeneration, and glial cell dysregulation. Our platform supports real-time, multiplexed tracking of disease progression and provides a scalable platform for longitudinal analyses studying disease mechanisms and targeted approaches to treatment.

neuroscience↗

bioRxiv2026

Trisomy 21 cerebral organoids exhibit Alzheimer's disease amyloid and apolipoprotein E co-pathologies

Adults with Down syndrome (DS) develop Alzheimers disease (AD) brain pathology by age 40 due to triplication of the Amyloid Precursor Protein (APP) gene on chromosome 21. Inheritance of the apolipoprotein E-e4 (APOE4) allele of the APOE gene on chromosome 19 remains the greatest genetic risk factor for AD in the typical population, yet its role in DS-associated AD (DS-AD) neuropathogenesis in people with DS is unclear. We generated human induced pluripotent stem cell (hiPSC)-derived neurons, astrocytes, and cerebral organoids (COs) using cells from people with DS and from euploid individuals. Aged DS COs were smaller than aged euploid COs and showed robust amyloid-{beta} neuropathology that was positively correlated with the levels of apoE expression. We then captured extracellular vesicles (EVs) from the conditioned media of COs and observed a decrease in the levels of secreted AD-related proteins, including amyloid, contained within the EVs and in the media from which the EVs were isolated. We also identified distinct neuronal and astrocytic gene expression signatures in DS COs relative to euploid COs, including a set of genes known to interact with both APOE and APP at the gene and/or protein levels. Lastly, we determined that, despite differences in the expression levels of the specific genes involved, several common pathways were upregulated in T21 hiPSC-derived neurons, astrocytes, and COs, including apoptosis, the endolysosome, and structural stabilization pathways. Taken together, our findings provide novel insights into molecular mechanisms that may contribute to DS-AD and indicate that apoE plays an important role in the disease process.

neuroscience↗

bioRxiv2021

Traumatic Brain Injury Exacerbates Alzheimer's Disease Pathology in the Retinas of TgF344-AD Rats

Alzheimers disease (AD) is a neurodegenerative condition that affects 6.2 million people age 65 and older in the U.S. alone, and is the leading cause of dementia. Moreover, AD can lead to visual impairment, and AD histopathology also manifests in the retina. However, the factors that modulate AD pathophysiology and lead to varied susceptibility and presentation in the population are not well understood. In this context, traumatic brain injury (TBI), which can arise from sport concussions, military combat, and other causes, is associated with a 2.3-fold higher risk of developing AD and AD-related dementias (ADRD). Thus, we set out to evaluate the effects of TBI, AD, and their combination, on retinal histopathology. Several animal models have been developed to investigate the mechanisms underlying AD, but many have been limited by imperfect recapitulation of human pathology, and no model of TBI-associated AD (AD-TBI) has been characterized. To address this gap, we generated an innovative model of AD-TBI by taking advantage of a transgenic rat model (Tg-F344-AD) shown to recapitulate the main features of human AD pathology, and combining it with a twotime unilateral controlled cortical impact paradigm to mimic repetitive mild TBI (rmTBI). Histopathological analyses at four months post-impact confirm the presence of AD markers in transgenic retinas, and an increased severity of AD pathology due to TBI. Together, these results contribute to our understanding of the effects of TBI on AD retinopathy, with implications for patient care and therapeutic development.

neuroscience↗

bioRxiv2021

Kif11 overexpression rescues cognition, long-term potentiation, and spine defects in mouse and cell models of Alzheimer's disease

Competitive inhibition of kinesin motor proteins by amyloid-beta (A{beta}) may contribute to alterations in the neuronal microtubule cytoskeleton that can disrupt plasticity mechanisms required for learning and memory, such as long-term potentiation (LTP), thus contributing to synaptic dysfunction and cognitive impairments associated with Alzheimers disease (AD). Here, we tested the hypothesis that overexpression of the microtubule motor protein KIF11 (Kinesin-5/Eg5) will rescue A{beta}-mediated synaptic dysfunction and cognitive impairments. We found that overexpression of Kif11 prevented spatial learning and LTP deficits in the 5xFAD mouse model of AD and rescued A{beta}-mediated decreases in postsynaptic dendritic spine density in neuronal cultures. Together, these data suggest that KIF11 function is important for preserving synaptic structures and functions that are critical for learning and memory and for protection against A{beta}-mediated loss of cognition in AD. HighlightsO_LIDeficits in cognition and long-term potentiation in the 5xFAD mouse model of Alzheimers disease are prevented by Kif11 overexpression. C_LIO_LIA{beta}-mediated dendritic spine loss is blocked by Kif11 overexpression. C_LI

neuroscience↗

bioRxiv2021

Imipramine and olanzapine block apoE4-catalyzed polymerization of Aβ and show evidence of improving Alzheimer's disease cognition

The apolipoprotein E (APOE) {varepsilon}4 allele confers the strongest risk for late-onset Alzheimers disease (AD) besides age itself, but the mechanism(s) underlying this risk are debated. The critical test of any proposed AD mechanism is whether it leads to effective treatments. We developed a high-throughput assay to identify inhibitors of apoE4-catalyzed polymerization of the amyloid {beta} (A{beta}) peptide into neurotoxic fibrils. Screening a human drug library, we identified five non-toxic, blood-brain-barrier-permeable hit compounds that reduced apoE4-promoted A{beta} and tau neuropathology in cultured neurons. Two hit compounds, imipramine and olanzapine, but not other (non-hit) antipsychotics or antidepressants, when prescribed to AD patients for their normal clinical indications, led to improvements in cognition and clinical diagnosis. Imipramine and olanzapine have no structural, functional, or clinical similarities other than their ability to inhibit apoE4-catalyzed A{beta} polymerization, thus identifying this mechanism as an essential contribution of apoE4 to AD. One Sentence SummaryHigh-throughput drug screens, studies in Alzheimers disease cell culture models, and analyses of human clinical data identified inhibitors of the apoE4-A{beta} interaction as a novel class of Alzheimers disease therapeutics.

neuroscience↗