Summary
Aging is a major risk factor for Alzheimer’s disease (AD). Progression of AD has been linked with 1) an
abnormally high systemic and mucosal inflammation in elderly organs, including the brain; 2) dysfunctional
permeability (leakiness) in gut and blood-brain barriers (BBB); 3) suppressed autonomic (vagus) nerve activity
linked with increased inflammation; and 4) increased amyloid beta (Aß) and Tau accumulation. However, no
currently available drugs target aging-related gut and BBB leakiness and/or vagus nerve suppression, to reduce
inflammation. Intriguingly, metformin (a safe and clinically approved drug commonly used to treat diabetes)
reduces gut and BBB leakiness and consequent inflammation to attenuate AD. This research proposal is
designed to identify the mechanisms by which metformin reduces gut and BBB leakiness and/or vagus nerve
function to halt inflammation and AD progression. Our preliminary studies in older mice established that
metformin decreased gut leakiness and inflammation and modulated gut microbiota toward increased production
of butyrate, a beneficial microbial metabolite and indicator of healthy microbiota. Metformin also improved
cognitive function and reduced inflammation and AD markers in the brains of older and AD transgenic (APP/PS1)
mice. These results demonstrate that metformin modulates gut-brain axis and reduces AD progression, but how
metformin causes these changes is not known. We hypothesize that metformin beneficially modulates gut
microbiota to suppress gut leakiness and inflammation and reduce AD progression. Mechanistically, we
hypothesize that metformin-mediated suppression of inflammation in gut are mediated by (i) stimulating vagus
nerve in the gut and/or (ii) reducing BBB leakiness, which reduces brain inflammation and AD progression. Three
Specific Aims test this hypothesis. In Aim 1, to determine whether metformin-modified gut microbiota is causal
for its effects to ameliorate AD, we will transplant fecal microbiota from metformin-treated and control AD mice
into gut-cleansed APP/PS1 mice (murine model of AD), and assess markers of gut and brain inflammation, gut
permeability, and AD progression. In Aim 2, we will assess whether metformin-induced changes in gut involves
(i) vagus nerve and/or (ii) BBB permeability to reduce brain inflammation and AD progression. In Aim 3, we will
assess whether metformin can delay or treat the pathology of AD by treating adults and older APP/PS1 mice
with metformin as AD progresses. Outcomes will establish proof-of-concept and provide the critical preclinical
data to support metformin as a therapy to prevent AD progression. Led by an NIH-trained new investigator, in
concert with multidisciplinary experts in cutting-edge technologies, this study is timely in addressing the RFA-
AG-20-044 (The Biological Mechanisms of Metformin Effects on Aging and Longevity- R01, Clinical Trial Not
Allowed). With this study, we will establish the biological mechanism(s) by which metformin can be a potential
new therapy for aging-related AD, a debilitating public health problem in older adults.