Gut microbiota and circadian rhythm in Alzheimer's disease pathophysiology: a review and hypothesis on their association

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease and the leading cause of dementia worldwide. Different pathologic changes have been introduced to be involved in its progression. Although amyloid-β (Aβ) deposition and tau hyperphosphorylation and aggregation are mainly considered the main characterizations of AD, several other processes are involved. In recent years, several other changes, including alterations in gut microbiota proportion and circadian rhythms, have been noticed due to their role in AD progression. However, the exact mechanism indicating the association between circadian rhythms and gut microbiota abundance has not been investigated yet. This paper aims to review the role of gut microbiota and circadian rhythm in AD pathophysiology and introduces a hypothesis to explain their association.

Fig. 1. Regulators of circadian rhythm in mammalian cells.

CLOCK-BMAL1 complex translocates to the nucleus and binds to E-box elements to activate the expression of Cry, PER, RPR, and REV-ERB as the negative regulators of primary complex activity. CRY1/2 cryptochrome, PER period, ROR retinoid-related orphan receptor, REV-ERB reverse erythroblastosis virus α.

Fig. 2. Gut-brain axis and circadian rhythm association.

Aberrant activity of SIRT1, MAPK, and GSK-3 results in altered BMAL1 activity in AD. On the other hand, disruption in BMAL1 activities may contribute to altered IgA secretion and gut microbiota abundance. This process induced Aβ deposition, neuroinflammation, and BBB disruption leading to AD progression. AD Alzheimer’s disease, BMAL1 brain and muscle ARNT-Like 1, GSK-3 glycogen synthase kinase, MAPK mitogen-activated protein kinases, SIRT1 Sirtuin 1.