A comprehensive multiomics approach toward understanding the relationship between aging and dementia.

Antonio Currais,Aaron Armando,Marguerite Prior,Richard Dargusch,Daniel Daugherty,Oswald Quehenberger,Pamela Maher,Max Chang,Catherine Farrokhi,David Schubert,Joshua Goldberg

doi:10.18632/aging.100838

Antonio Currais, Aaron Armando + Show 9 more

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https://doi.org/10.18632/aging.100838

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Abstract

Because age is the greatest risk factor for sporadic Alzheimer's disease (AD), phenotypic screens based upon old age-associated brain toxicities were used to develop the potent neurotrophic drug J147. Since certain aspects of aging may be primary cause of AD, we hypothesized that J147 would be effective against AD-associated pathology in rapidly aging SAMP8 mice and could be used to identify some of the molecular contributions of aging to AD. An inclusive and integrative multiomics approach was used to investigate protein and gene expression, metabolite levels, and cognition in old and young SAMP8 mice. J147 reduced cognitive deficits in old SAMP8 mice, while restoring multiple molecular markers associated with human AD, vascular pathology, impaired synaptic function, and inflammation to those approaching the young phenotype. The extensive assays used in this study identified a subset of molecular changes associated with aging that may be necessary for the development of AD.

Highlights

IntroductionOur laboratory uses a drug discovery paradigm based upon a set of cell-based screening assays that mimic numerous aspects of old age-associated neurodegeneration and Alzheimer’s disease (AD) pathology [1]
There is currently no drug to prevent or slow down the progression of Alzheimer’s disease (AD) pathology
Given the sevenmonth duration of the feeding paradigm, the effect of the J147 diet could only be assessed in old SAMP8 mice, and age-related changes were defined by comparison to the young SAMP8 animals

Summary

Introduction

Our laboratory uses a drug discovery paradigm based upon a set of cell-based screening assays that mimic numerous aspects of old age-associated neurodegeneration and AD pathology [1]. This approach has led to the identification of J147, a very potent neuroprotective small molecule that is orally active in transgenic human familial AD (hFAD) animal models [2, 3]. One model of aging is the senescence-accelerated prone 8 (SAMP8) mouse, that has a progressive, ageassociated decline in brain function similar to human AD patients [5, 6]. These insights could lead to novel interventions for old ageassociated sporadic AD

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