2023 Alzheimer's Association Research Grant (AARG)

Misalignment in Circadian Glymphatic System as Trigger of Neurodegeneration

How are inflammation, circadian rhythms, and waste clearance in the brain linked? 

Cristina Lanni, Ph.D.
University of Pavia
Pavia, Italy

Background

Alzheimer’s is associated with hallmark brain changes including the accumulation of the proteins beta-amyloid and tau into abnormal plaques and tangles, respectively. While scientists do not know exactly why the accumulation of beta-amyloid and tau occurs, one factor may be through impairments in the brain’s waste removal system, known as the glymphatic system.

In cognitively unimpaired individuals, the glymphatic system successfully removes waste products produced by nerve cells from the brain. This process is regulated by circadian rhythms (sleep/wake cycle), natural biological changes that occur over an approximately 24-hour cycle. The glymphatic system clears most waste during sleep. Individuals with Alzheimer’s often experience sleep disruptions or poor sleep patterns years before symptoms of cognitive impairment. 

Brain inflammation has been identified as an early brain change in Alzheimer’s and has been linked to brain cell damage and cognitive decline in the early stages of the disease. Recent evidence suggests that inflammation in areas outside the brain (called peripheral inflammation) may also affect Alzheimer's progression.
Dr. Cristina Lanni and colleagues believe that a misalignment of circadian rhythms, induced by peripheral inflammation, may disrupt the glymphatic system and trigger early brain cell death in Alzheimer’s.

Research Plan

Dr. Lanni and team will study genetically engineered Alzheimer’s-like mice with inflammation of the colon. The researchers will use transcriptomics (the study of all the genes that are “turned on” in a cell) to identify which brain cells and which genes related to glymphatic function are most impacted by peripheral inflammation. They will also use brain scans (magnetic resonance imaging, MRI) to study glymphatic function in the mice. In addition, Dr. Lanni and team will identify specific brain areas that may be primarily affected by the glymphatic dysfunction in the brain.

Impact

The results may shed light on how inflammation in the body impacts the sleep/wake cycle and waste clearance in the brain. The findings may contribute to new avenues for dementia prevention efforts.