Biology subjects

Sillau, S.

Publications and source records attributed to Sillau, S..

3 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↗

bioRxiv2021

Pro-inflammatory Cytokine GM-CSF Improves Learning/Memory and Brain Pathology in Dp16 Down Syndrome Mice and Improves Learning/Memory in Wild-Type Mice

Down syndrome (DS) is characterized by chronic neuroinflammation, peripheral inflammation, astrogliosis, imbalanced excitatory/inhibitory neuronal function, and cognitive deficits in both humans and mouse models. Suppression of inflammation has been proposed as a therapeutic approach to treating DS co-morbidities, including intellectual disability (DS/ID). Conversely, we discovered previously that treatment with the pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) improved cognition and reduced biomarkers of brain pathology in humans with Alzheimers disease (AD), another inflammatory disorder, and in a mouse model of AD. To investigate the effects of GM-CSF treatment on DS/ID, we assessed behavior and brain pathology in 12-14 month-old DS mice (Dp[16]1Yey) and their wild-type (WT) littermates, neither of which develop amyloid, and found that GM-CSF treatment improved performance in the radial arm water maze in both Dp16 and WT mice compared to placebo. Dp16 mice also showed abnormal astrocyte morphology and aggregation and fewer calretinin-positive interneurons, both of which were improved by GM-CSF treatment. These findings suggest that stimulating and/or modulating inflammation and the innate immune system with GM-CSF treatment may enhance cognition in both people with DS/ID and in the typical aging population.

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↗