Alzheimer’s Disease: Current Perspectives and Advances in Physiological Modeling

Abstract

Though Alzheimer’s disease (AD) is the most common cause of dementia, complete disease-modifying treatments are yet to be fully attained. Until recently, transgenic mice constituted most in vitro model systems of AD used for preclinical drug screening; however, these models have so far failed to adequately replicate the disease’s pathophysiology. However, the generation of humanized APOE4 mouse models has led to key discoveries. Recent advances in stem cell differentiation techniques and the development of induced pluripotent stem cells (iPSCs) have facilitated the development of novel in vitro devices. These “microphysiological” systems—in vitro human cell culture systems designed to replicate in vivo physiology—employ varying levels of biomimicry and engineering control. Spheroid-based organoids, 3D cell culture systems, and microfluidic devices or a combination of these have the potential to replicate AD pathophysiology and pathogenesis in vitro and thus serve as both tools for testing therapeutics and models for experimental manipulation.

Human and mouse cortical astrocytes: a comparative view from development to morphological and functional characterization

“…Advances in human induced pluripotent stem cell (hIPSC) technology are being adapted to astrocyte research. At present, astrocytes can be generated in 2D layers or even in 3D systems, such as spheroids or organoids ( Sloan et al, 2017 ; Tchieu et al, 2019 ; Boder and Banerjee, 2021 ), or can be grown in mouse chimeric brains ( Han et al, 2013 ; Osipovitch et al, 2019 ). Interestingly, astrocytes generated from patient derived-hiPSC have been shown to recapitulate some pathological phenotypes, such as lipid metabolism dysregulation, altered signaling, or variation in the content of extracellular vesicles ( Lin et al, 2018 ; di Domenico et al, 2019 ; Varcianna et al, 2019 ).…”

Cognitive Decline: Current Intervention Strategies and Integrative Therapeutic Approaches for Alzheimer’s Disease

“…Current therapeutic trials are replacing neurons that have been lost in the neurodegenerative phases of AD with stem cells. Stem cell-based therapy is both a suitable and effective restorative strategy for AD treatment as well as several neurodegenerative diseases, based on the neurogenesis capacities that stem cells hold [28,29]. There is a significant role played by intercellular binding proteins and glial cells when setting the extracellular conditions of neurons.…”

“…There is a significant role played by intercellular binding proteins and glial cells when setting the extracellular conditions of neurons. The extensive deterioration of astrocytes, oligodendrocytes, and microglia, which all provide strength to the neuronal networks in the central nervous system, contributes to the extensive neuronal loss associated with AD [28,29]. The regeneration or transplantation, in situ, of destroyed neurons has provided anticipation of the restructuring of the central nervous system's reliability and reducing the deterioration of the mental ability of patients with AD [28,29].…”

An update on stem cell and stem cell-derived extracellular vesicle-based therapy in the management of Alzheimer’s disease

“…Engineered neurogenesis have been explored by various researchers by doping biomaterials in the form of nanoparticles, microspheres, nanotubes, micro-columns, and gels with cellular transplantation to support, enhance, and facilitate neurogenesis [ 124 , 125 ]. Poudel et al elaborated the carrier materials [liposomes, micelles, solid lipid nanoparticles, polymeric nanoparticles, dendrimers, nanoemulsions, and inorganic nanoparticles] for neuronal regeneration in AD disease [ 126 ].…”