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.

Sildenafil for the Treatment of Alzheimer’s Disease: A Systematic Review

“…Alzheimer's disease (AD) is the leading cause of dementia worldwide, and AD patients and their families urgently require novel therapeutics to prevent and slow the progression of this devastating disorder. Hallmarks of AD include amyloid-␤ (A␤) peptide secretion and deposition into neuritic plaques, tau protein hyperphosphorylation and neurofibrillary tangle formation, metal ion dyshomeostasis [1][2][3][4][5][6][7][8][9], oxidative stress and lipid, nucleic acid, and protein damage [10][11][12][13], abortive cell cycle reentry [14][15][16][17][18][19][20][21][22][23][24][25][26], neuroinflammation and microbial dysbiosis [27][28][29][30][31][32][33], insulin resistance [34,35], cerebrovascular dysfunction [36][37][38], synaptic dysfunction [39,40], neuronal loss, endoplasmic reticulum stress [41][42][43][44], and mitochondrial dysfunction [...…”

Biomimetic Nanocarrier Targeting Drug(s) to Upstream-Receptor Mechanisms in Dementia: Focusing on Linking Pathogenic Cascades

“…Particularly noteworthy is more recent research [59,60] indicating that chronic inflammatory stimulus in the gut may induce (e.g., via serum amyloid A (SAA)) the release of proinflammatory cytokines. At the same time, increased BBB permeability due to aging (or dysfunction), in turn, allows these proinflammatory cytokines to enter the brain, inducing glia reactivity [59,60].…”

“…Particularly noteworthy is more recent research [59,60] indicating that chronic inflammatory stimulus in the gut may induce (e.g., via serum amyloid A (SAA)) the release of proinflammatory cytokines. At the same time, increased BBB permeability due to aging (or dysfunction), in turn, allows these proinflammatory cytokines to enter the brain, inducing glia reactivity [59,60]. These recent findings and various past studies indicate that inflammation plays an important role in the process of Aβ deposition and, therefore, the inhibition of inflammatory cascades may attenuate amyloidogenic processes-such as Alzheimer's disease [61] (cf.…”

Biomaterial to Improve Drug Delivery in Alzheimer's Disease: Linking Major Pathogenic Pathways

“…below] ) the release of proinflammatory cytokines. At the same time, increased BBB permeability due to aging (or dysfunction), in turn, allows these proinflammatory cytokines to enter the brain, inducing glia reactivity [70,71]. ( Note too that unlike other acute phase proteins, which are synthesized primarily in the liver, acute-phase SAA is also markedly expressed at local sites of tissue inflammation.…”