The Post-amyloid Era in Alzheimer's Disease: Trust Your Gut Feeling

Abstract

The amyloid hypothesis, the assumption that beta-amyloid toxicity is the primary cause of neuronal and synaptic loss, has been the mainstream research concept in Alzheimer's disease for the past two decades. Currently, this model is quietly being replaced by a more holistic, "systemic disease" paradigm which, like the aging process, affects multiple body tissues and organs, including the gut microbiota. It is well-established that inflammation is a hallmark of cellular senescence; however, the infection-senescence link has been less explored. Microbiota-induced senescence is a gradually emerging concept promoted by the discovery of pathogens and their products in Alzheimer's disease brains associated with senescent neurons, glia, and endothelial cells. Infectious agents have previously been associated with Alzheimer's disease, but the cause vs. effect issue could not be resolved. A recent study may have settled this debate as it shows that gingipain, a Porphyromonas gingivalis toxin, can be detected not only in Alzheimer's disease but also in the brains of older individuals deceased prior to developing the illness. In this review, we take the position that gut and other microbes from the body periphery reach the brain by triggering intestinal and blood-brain barrier senescence and disruption. We also surmise that novel Alzheimer's disease findings, including neuronal somatic mosaicism, iron dyshomeostasis, aggressive glial phenotypes, and loss of aerobic glycolysis, can be explained by the infection-senescence model. In addition, we discuss potential cellular senescence targets and therapeutic strategies, including iron chelators, inflammasome inhibitors, senolytic antibiotics, mitophagy inducers, and epigenetic metabolic reprograming.

Keywords: amyloid hypothesis; infection; inflammation; microbiome; senescence.

Graphical Abstract

Proposed Alzheimer's disease (AD) pathogenesis: (1) Age-related gut microbiota shift leads to the upregulation of inflammagenic, lipopolysaccharide (LPS)-shedding microbial species. (2) These microorganisms activate nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes in intestinal epithelial cells (IECs), generating interleukin-1β (IL-1β), IL-18, and caspase-1. (3) IL-1β increases the permeability of intestinal and blood-brain barrier, allowing pathogen translocation into the body tissues and organs, including the brain. (4) Microorganisms and LPS induce cellular senescence in neurons, microglia, and astrocyte AD pathology.

Figure 1

Microbes or LPS that access the CNS comprise “danger” signals, triggering an innate immune response: the release of β-amyloid by astrocytes to opsonize “the intruder,” preparing it for phagocytosis (Zhan et al., 2018). The LPS–β-amyloid complex is subsequently engulfed by microglia, eliminating the “danger.” Microglial TREM-2, a β-amyloid receptor, initiates phagocytosis by binding the entire complex (Zhao et al., 2018). This mechanism may explain the reason TREM-2 genetic variants (with loss of function) present with impaired phagocytosis and β-amyloid accumulation (Guerreiro et al., ; Zhan et al., 2018).

Figure 2

M cells interact with luminal microbes, introducing microbial antigens to the T and B cells, engendering tolerance via Tregs and IL-10 secretion. M cells promote the expression of the mucosal protector, SIgA. L cells synthesize IECs protecting biomolecules GLP-1 and GLP-2. Senescent ECs cause endothelial disruption, allowing pathogens into the circulatory system, from where they find their way into the CNS.

Figure 3

Schematic representation of NLRP3 activation by microbes or their molecules. Microbes or LPS binds to TLR-4, activating the nuclear NF-kB that primes NLRP3. The second step necessary for NLRP3 activation can be composed of various exogenous or endogenous stimuli, including ROS, ATP, DNA, defective mitochondria, iron, and toxins. Assembled inflammasome activates caspase-1, which in turn cleaves immature IL-1β and IL-18 into their active forms. Caspase-1 and IL-18 have been involved in AD pathogenesis, while IL-1β disrupts the BBB, facilitating brain translocation of gut microbes.

Figure 4

Potential senotherapeutic interventions in AD and the steps at which they may operate. NLRP3 end products, IL-1β, IL-18, and caspase-1, inhibit autophagy and mitophagy, contributing to the accumulation of senescent cells and damaged mitochondria. These, in turn, alter biological barriers, enabling microbial translocation and AG loss. Excess iron induces DNA and mtDNA damage, activating NLRP3 with subsequent cellular senescence.