Dhanasekaran, A. R. | Search bioRxiv

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↗

bioRxiv2020

The Aging Slow Wave: A Shifting Amalgam of Distinct Slow Wave and Spindle Coupling Subtypes Define Slow Wave Sleep Across the Human Lifespan

Study ObjectivesSlow wave and spindle coupling supports memory consolidation, and loss of coupling is linked with cognitive decline and neurodegeneration. Coupling is proposed to be a possible biomarker of neurological disease, yet little is known about the different subtypes of coupling that normally occur throughout human development and aging. Here we identify distinct subtypes of spindles within slow wave upstates and describe their relationships with sleep stage across the human lifespan. MethodsCoupling within a cross-sectional cohort of 582 subjects was quantified from stages N2 and N3 sleep across ages 6-88 years old. Results were analyzed across the study population via mixed model regression. Within a subset of subjects, we further utilized coupling to identify discrete subtypes of slow waves by their coupled spindles. ResultsTwo different subtypes of spindles were identified during the upstates of (distinct) slow waves: an "early-fast" spindle, more common in stage N2 sleep, and a "late-fast" spindle, more common in stage N3. We further found stages N2 and N3 sleep are composed of two discrete subtypes of slow waves, each identified by their unique coupled-spindle timing and frequency. The relative contribution of coupling subtypes shifts across the human lifespan, and a deeper sleep phenotype prevails during old age. ConclusionsDistinct subtypes of slow waves and coupled spindles form the composite of slow wave sleep. Our findings support a model of sleep-dependent synaptic regulation via discrete slow wave/spindle coupling subtypes and advance a conceptual framework for the development of coupling-based biomarkers in age-associated neurological disease. Statement of SignificanceSlow waves of nonrapid eye movement sleep couple with sleep spindles in a process hypothesized to support memory functions. This coupling has recently gained interest as a possible biomarker of cognitive aging and onset of Alzheimers disease. Most studies have been limited by an assumption that all slow waves (and coupled spindles) are fundamentally the same physiological events. Here we demonstrate that distinct subtypes of slow waves and their coupled spindles can be identified in human sleep. A mixture of different slow wave and spindle subtypes shifts in composition during lighter versus deeper sleep, and aging favors the deep sleep subtypes. These data should inform any future attempts to use slow wave sleep as a biomarker or clinical interventional target.

neuroscience↗