Methods for treating aging-related cognitive decline and reducing risk of AD/ADRD by enhancing the endogenous expression of adropin

Project Summary
A demographic transition that is currently underway in the United States will require an increased investment in
the managed care of the elderly population. By 2030, people over 65 will account for over 20% of the population,
and as many as 1 in 3 people will develop some form of dementia after their 65th birthday. However, society has
yet to determine how to manage the burden of providing round-the-clock care for elderly people with memory
impairment. Developing pharmacotherapies that prolong the period of independence of elderly people with the
early stages of cognitive decline will have a significant impact. We have identified adropin, a small peptide that
is abundant in the brain, as a potential lead for developing drugs that delay aging-related cognitive decline.
Several lines of evidence suggest that low adropin activity in the brain predisposes to aging-related cognitive
decline and that increasing adropin activity would be beneficial. In humans, low circulating adropin levels are
predictive of cognitive decline in older adults. Moreover, in mouse studies, interventions that increase adropin
levels have been shown to protect against aging-related cognitive decline. However, gaps in knowledge on how
adropin acts at a cellular level are a barrier to developing drugs based on adropin. This proposal addresses this
barrier by developing an antisense-oligonucleotide (ASO) therapy to boost expression of the endogenous gene.
The central hypothesis tested by the proposal is that ASO which inhibit the interaction of the mRNA encoding
adropin (ENHO) with miR-29, a microRNA that inhibits expression, will increase adropin levels in brain. Based
on preclinical experiments using a transgenic mouse approach to prevent aging-related decline in adropin protein
levels, ASO that specifically target the interaction of miR-29 with ENHO will increase adropin activity and
significantly improve cognitive performance in aged mice. This exploratory proposal will identify ‘lead’ ASO
sequences targeting the ENHO-miR-29 interaction using cell-based assays and perform preclinical experiments
using old mice to demonstrate feasibility of the approach.

Grant Number: 1R21AG087308-01
NIH Institute/Center: NIH
Principal Investigator: Andrew Butler