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.
Highlights
Alzheimer’s disease (AD) is the most common cause of dementia, affecting an estimated 5.5 million people in the US alone (Mayeux and Stern, 2012)
Both neurons and astrocytes synthesize β-amyloid from amyloid precursor protein (APP), while phagocytic microglia prevent its accumulation by removing it via the triggering receptor expressed on myeloid cells-2 (TREM-2)
Accumulating evidence indicates that aging neurons activate a special senescence program, defined as senescence after differentiation (SAD), a phenotype marked by upregulation of β-galactosidase, lipofuscin, senescence-associated secretory phenotype (SASP), and IL-6 (Jurk et al, 2012; Naylor et al, 2012; Tan et al, 2014)
Summary
Alzheimer’s disease (AD) is the most common cause of dementia, affecting an estimated 5.5 million people in the US alone (Mayeux and Stern, 2012). Recent studies have reported co-localization of microorganisms with senescent neurons and glial cells in the brains of both AD patients and healthy older individuals, reviving the infectious hypothesis entertained by Alois Alzheimer himself (De Chiara et al, 2012; Bester et al, 2015; Itzhaki et al, 2016; Alonso et al, 2018; Fulop et al, 2018b; Kritsilis et al, 2018). Cellular senescence has been associated with the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes (Yamazaki et al, 2016; Zhang W. et al, 2017; Burton and Stolzing, 2018). The association of AD with iron dysmetabolism is welldocumented as, aside from microbial survival, this biometal was linked to tau pathology, reactive oxygen species (ROS), and TABLE 1 | Perceived inconsistencies in the amyloid cascade hypothesis emphasized by novel studies
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