The aggregation and accumulation of amyloid-β plaques and tau proteins in the brain have been central characteristics in the pathophysiology of Alzheimer’s disease (AD), making them the focus of most of the research exploring potential therapeutics for this neurodegenerative disease. With success in interventions aimed at depleting amyloid-β peptides being limited at best, a greater understanding of the physiological role of amyloid-β peptides is needed. The development of amyloid-β plaques has been determined to occur 10–20 years prior to AD symptom manifestation, hence earlier interventions might be necessary to address presymptomatic AD. Furthermore, recent studies have suggested that amyloid-β peptides may play a role in innate immunity as an antimicrobial peptide. These findings, coupled with the evidence of pathogens such as viruses and bacteria in AD brains, suggests that the buildup of amyloid-β plaques could be a response to the presence of viruses and bacteria. This has led to the foundation of the antimicrobial hypothesis for AD. The present review will highlight the current understanding of amyloid-β, and the role of bacteria and viruses in AD, and will also explore the therapeutic potential of antimicrobial and antiviral drugs in Alzheimer’s disease.

Sleep deprivation is a form of stress that provokes both inflammatory responses and neuropsychiatric disorders. Because persistent inflammation is implicated as a physiological process in anxiety disorders, we investigated the contributions of NLRP3 inflammasome signaling to anxiety and anxiolytic properties of flavanol diets in a model of chronic sleep deprivation. The results show a flavanol-rich dietary preparation (FDP) exhibits anxiolytic properties by attenuating markers of neuroimmune activation, which included IL-1β upregulation, NLRP3 signaling, and microglia activation in the cortex and hippocampus of sleep-deprived mice. Production of IL-1β and NLRP3 were critical for both anxiety phenotypes and microglia activation. Individual FDP metabolites potently inhibited IL-1β production from microglia following stimulation with NLRP3-specific agonists, supporting anxiolytic properties of FDP observed in models of sleep deprivation involve inhibition of the NLRP3 inflammasome. The study further showed sleep deprivation alters the expression of the circadian gene Bmal1, which critically regulated NLRP3 expression and IL-1β production.

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Background Brain organoids are self‐assembled 3D cell aggregates developed from pluripotent stem cells with various cell types and extracellular structures that resemble the embryonic human brain. Induced pluripotent stem cells (iPSC) based organoids show great promise in disease modeling applications. Our previous work has validated the use of novel polyphenolic compounds to combat neurodegenerative diseases in animal and traditional cell culture models. The goal of the present study is to continue to explore the development of a functional brain organoid system with microvasculature and a blood‐brain barrier using iPSCs. Method iPSCs were differentiated into neurons, astrocytes, pericytes, oligodendrocytes, brain microvascular endothelial cells, and other relevant cell types. The organoid was developed using previously published protocols. The blood‐brain barrier was constructed by co‐culturing the different cell types. Result In this ongoing study, we demonstrate the development of a more accurate and functional brain organoid system with microvasculature and a blood‐brain barrier using iPSCs. Conclusion Our organoid will serve as a model for neurodegenerative diseases, drug discovery and the screening of novel polyphenolic compounds from dietary flavanols which have been recently associated with reduced risk of developing Alzheimer’s Dementia.

Intronic G4C2 hexanucleotide repeat expansions of C9orf72 are the most common cause of familial variants of frontotemporal dementia / amyotrophic lateral sclerosis (FTD/ALS)1,2. G4C2 hexanucleotide repeat expansions (HREs) in C9orf72 undergo non-canonical repeat associated translation, producing dipeptide repeat (DPR) proteins, with various deleterious impacts on cellular homeostasis 3. While five different DPRs are produced, poly(glycine-arginine) (GR) is amongst the most toxic, and is the only DPR to accumulate in the associated clinically relevant anatomical locations of the brain 4,5. Previous work has demonstrated the profound effects of a poly(GR) model of c9FTD/ALS, including motor impairment, memory deficits, neurodegeneration, and neuroinflammation6. Neuroinflammation is hypothesized to be a driving factor in the disease course; microglia activation is present prior to symptom onset and persists throughout the disease7. Here, we establish the contributions of the NLRP3 inflammasome in the pathogenesis of FTD/ALS, resulting from a stress-induced neuronal-microglial crosstalk feedforward loop. In a mouse model of c9FTD/ALS, inflammasome-mediated inflammation was increased with microglial activation, cleavage of caspase-1, upregulation of Cxcl10, and production of IL-1β. We find that genetic ablation of Nlrp3 protected behavioral deficits and prevented neurodegeneration as seen in C57BL6J Wild Type mouse model of c9FTD/ALS. Ultimately, survival was improved by the genetic ablation of Nlrp3. Moreover, we identified the process by which neuronal stress signals induced by hexanucleotide expansions initiate an inflammatory cascade in microglia. These findings provide evidence of the integral role of inflammasome-mediated innate immunity in c9FTD/ALS pathogenesis, and suggest the NLRP3 inflammasome as a therapeutic target.