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Alzheimer’s disease (AD) is a highly complex neurodegenerative disorder and the current treatment strategies are largely ineffective thereby leading to irreversible and progressive cognitive decline in AD patients. AD continues to defy successful treatment despite significant advancements in the field of molecular medicine. Repeatedly, early promising preclinical and clinical results have catapulted into devastating setbacks leading to multi-billion dollar losses not only to the top pharmaceutical companies but also to the AD patients and their families. Thus, it is very timely to review the progress in the emerging fields of gene therapy and stem cell-based precision medicine. Here, we have made sincere efforts to feature the ongoing progress especially in the field of AD gene therapy and stem cell-based regenerative medicine. Further, we also provide highlights in elucidating the molecular mechanisms underlying AD pathogenesis and describe novel AD therapeutic targets and strategies for the new drug discovery. We hope that the quantum leap in the scientific advancements and improved funding will bolster novel concepts that will propel the momentum toward a trajectory leading to a robust AD patient-specific next generation precision medicine with improved cognitive function and excellent life quality.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the presence of intracellular neurofibrillary tangles (NFTs) containing hyper-phosphorylated tau, and the extracellular deposition of amyloid plaques (APs) with misfolded amyloid–β (Aβ) peptide. Glia maturation factor (GMF), a highly conserved pro-inflammatory protein, isolated and cloned in our laboratory has been shown to activate glial cells leading to neuroinflammation and neurodegeneration in AD. We hypothesized that inflammatory reactions promoted by NLRP3-Caspase-1inflammasome pathway trigger dysfunction in autophagy and accumulation of Aβ which is amplified and regulated by GMF in AD. In this study, using immunohistochemical techniques we analyzed components of the NLRP3 inflammasome and autophagy-lysosomal markers in relation to Aβ, p-tau and GMF in human post-mortem AD and age-matched non-AD brains. Tissue sections were prepared from the temporal cortex of human post-mortem brains. Here, we demonstrate an increased expression of the inflammasome components NLRP3 and Caspase-1 and the products of inflammasome activation IL-1β and IL-18 along with GMF in the temporal cortex of AD brains. These inflammasome components and the pro-inflammatory cytokines co-localized with GMF in the vicinity and periphery of the amyloid plaques and NFTs. Moreover, using double immunofluorescence staining, AD brain displayed an increase in the autophagy SQSTM1/p62 and LC3 positive vesicles and the lysosomal marker LAMP1 that also co-localized with GMF, amyloid beta and hyper-phosphorylated p-tau. Our results indicate that in AD, the neuroinflammation promoted by the NLRP3 inflammasome may be amplified and regulated by GMF, which further impairs clearance of protein aggregates mediated by the autophagosomal pathway.

Inflammatory responses are increasingly implicated in the pathogenesis of neurodegenerative diseases such as in Alzheimer's disease (AD). Interleukin-33 (IL-33), a member of IL-1 family, is constitutively expressed in the central nervous system and thought to be an important mediator of glial cell response to neuropathological lesions. Proinflammatory molecules are highly expressed at the vicinity of amyloid plaques (APs) and neurofibrillary tangles (NFTs), the hallmarks of AD pathology. We have investigated the expression of IL-33 and ST2 in relation to APs and NFTs in human AD and non-AD control brains by immunohistochemistry. Sections from the entorhinal cortex, where APs and NFTs appear in early stages of AD, were used for immunohistochemistry. Mouse primary astrocytes were cultured and incubated with amyloid-β1-42 (Aβ1-42), component of plaque for 72 h and analyzed for the expression of IL-33 by flow cytometry. We found strong expression of IL-33 and ST2 in the vicinity of Aβ and AT8 labelled APs and NFTs respectively, and in the glial cells in AD brains when compared to non-AD control brains. IL-33 and ST2 positive cells were also significantly increased in AD brains when compared to non-AD brains. Flow cytometric analysis revealed incubation of mouse astrocytes with Aβ1-42 increased astrocytic IL-33 expression in vitro. These results suggest that IL-33, an alamin cytokine, may induce inflammatory molecule release from the glial cells and may play an important role in the pathogenesis of AD.