Altered ENS Neuroimmune Interactions Disrupt Gastrointestinal Motility in Alzheimers Disease

Abstract
Gastrointestinal (GI) disorders including constipation and fecal incontinence are commonly found in patients with
Alzheimer’s disease (AD), the most common cause of dementia. These same disorders are also frequently
encountered in the elderly, raising the possibility that a common process may underlie gut disturbances for both
AD and aging. In humans with AD and AD animal models, amyloid-β (Aβ) plaques, one of the disease hallmarks,
have been detected in the enteric nervous system (ENS), an autonomous branch of the peripheral nervous
system that spans the GI tract and regulates gut motility. Aβ gut accumulation appears to cause ENS
neuroinflammation and impaired gut contractility but current literature precludes definitive conclusion. Whether
and how AD involves the gut is of increasing importance given emerging reports that neurodegenerative
disorders are transmitted from the gut to the brain. The proposed multidisciplinary study will integrate the
science of AD with the basic biology of aging. We found that age-related changes to muscularis
macrophages (MMs), a population of tissue-resident macrophages in the ENS, drive geriatric ENS inflammation,
which is associated with disruption of GI motility and impaired cognition. This MM alteration is dependent on
factors in the microbiota and mirrors an AD diseased state found in microglia, the predominant macrophage
population of the brain. Following on these findings, we posit that AD causes MM changes similar to those
seen in geriatric subjects that result in ENS neuroinflammation, altered GI motility and impaired
cognition, and depend on host-microbiota interactions. This hypothesis will be tested with three aims
performed in the APP/PS1 AD mouse model. First, the investigators will evaluate whether AD causes ENS
neuroimmune changes characterized by a MM geriatric disease state (GDS). They will assess whether
alterations in MMs lead to geriatric ENS neuroinflammation with infiltration of immune cells and elevated pro-
inflammatory cytokines, and enteric neuronal loss. Second, the investigators will assess whether disruption in
gut motility precedes impaired cognition. Finally, using experimental manipulation of the microbiota, the
investigators will explore the role of host-microbiota interactions in AD-associated GI disease and their
relationship to cognition. Specifically, the investigators will examine whether and how AD disease progression
is affected by chronic antibiotics, fecal microbiota transplantation of stool from young or old mice, or probiotic
supplementation with Akkermansia mucinophila, a microbiota component reduced in old mice.
Successful completion of the proposed studies will identify critical pathophysiological pathways that affect the
gut and precede cognitive decline. The results will inform novel prevention and intervention strategies for AD
and aging-associated dementia.

Grant Number: 5R01AG068394-06
NIH Institute/Center: NIH
Principal Investigator: Laren Becker