New approaches for understanding the potential role of microbes in Alzheimer's disease

Abstract

Alzheimer's disease (AD) involves a complex pathological process that evolves over years, and its etiology is understood as a classic example of gene-environment interaction. The notion that exposure to microbial organisms may play some role in AD pathology has been proposed and debated for decades. New evidence from model organisms and -omic studies, as well as epidemiological data from the recent COVID-19 pandemic and widespread use of vaccines, offers new insights into the "germ hypothesis" of AD. To review new evidence and identify key research questions, the Duke/University of North Carolina (Duke/UNC) Alzheimer's Disease Research Center hosted a virtual symposium and workshop: "New Approaches for Understanding the Potential Role of Microbes in Alzheimer's disease." Discussion centered around the antimicrobial protection hypothesis of amyloid accumulation, and other mechanisms by which microbes could influence AD pathology including immune cell activation, changes in blood-brain barrier, or direct neurotoxicity. This summary of proceedings reviews the content presented in the symposium and provides a summary of major topics and key questions discussed in the workshop.

Keywords: Immune; Infection; Inflammation; Microbiome; Neurodegeneration; Pathogen.

Fig. 1

Legend. Every human brain is potentially exposed to an array of microbial organisms (e.g. bacteria, fungi, viruses), which includes infectious agents from the environment or normal flora within the human microbiome. This figure illustrates a number of plausible mechanisms, at the cellular level, by which microbes could influence brain health and/or drive specific Alzheimer's disease pathology. In the center are amyloid plaques which are encasing and neutralizing pathogens that have gained entry to the brain parenchyma (as discussed in Section 1.0). Amyloid plaques are associated with a neuron that exhibits perinuclear tauopathy and with an activated microglial cell, demonstrating that the amyloid cascade of AD pathology has been initiated. The microglia and astrocytes are further activated by other microbes or microbe-derived particles (Section 5.0). The double-stranded RNA (dsRNA) from a retrotransposon (reactivated retrovirus), which was presumably released from the destabilized nucleus of a tau-damaged neuron, is activating a microglial cell (Section 6.0). A lipopolysaccharide (LPS) toxin released by gut microflora is on the blood side of the blood brain barrier, but it is activating brain-side microglia via pericytes or activated macrophages that cross the barrier (Section 7.0). Similarly, pathogenic microbes (Section 5.0) such as COVID-19 viruses (Sections 2.0-2.2), could stimulate brain immune cells and cause neuroinflammation, whether or not they cross the blood-brain barrier.