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Abstract As current treatments for Alzheimer's disease (AD) lack disease‐modifying interventions, novel therapies capable of restraining AD progression and maintaining better brain function have great significance. Anti‐inflammatory extracellular vesicles (EVs) derived from human induced pluripotent stem cell (hiPSC)‐derived neural stem cells (NSCs) hold promise as a disease‐modifying biologic for AD. This study directly addressed this issue by examining the effects of intranasal (IN) administrations of hiPSC‐NSC‐EVs in 3‐month‐old 5xFAD mice. IN administered hiPSC‐NSC‐EVs incorporated into microglia, including plaque‐associated microglia, and encountered astrocyte soma and processes in the brain. Single‐cell RNA sequencing revealed transcriptomic changes indicative of diminished activation of microglia and astrocytes. Multiple genes linked to disease‐associated microglia, NOD‐, LRR‐, and pyrin domain‐containing protein 3 (NLRP3)‐inflammasome and interferon‐1 (IFN‐1) signalling displayed reduced expression in microglia. Adding hiPSC‐NSC‐EVs to cultured human microglia challenged with amyloid‐beta oligomers resulted in similar effects. Astrocytes also displayed reduced expression of genes linked to IFN‐1 and interleukin‐6 signalling. Furthermore, the modulatory effects of hiPSC‐NSC‐EVs on microglia in the hippocampus persisted 2 months post‐EV treatment without impacting their phagocytosis function. Such effects were evidenced by reductions in microglial clusters and inflammasome complexes, concentrations of mediators, and end products of NLRP3 inflammasome activation, the expression of genes and/or proteins involved in the activation of p38/mitogen‐activated protein kinase and IFN‐1 signalling, and unaltered phagocytosis function. The extent of astrocyte hypertrophy, amyloid‐beta plaques, and p‐tau were also reduced in the hippocampus. Such modulatory effects of hiPSC‐NSC‐EVs also led to better cognitive and mood function. Thus, early hiPSC‐NSC‐EV intervention in AD can maintain better brain function by reducing adverse neuroinflammatory signalling cascades, amyloid‐beta plaque load, and p‐tau. These results reflect the first demonstration of the efficacy of hiPSC‐NSC‐EVs to restrain neuroinflammatory signalling cascades in an AD model by inducing transcriptomic changes in activated microglia and reactive astrocytes.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, emerged in December 2019, sparking a global health crisis. While initially recognized as a respiratory illness, it has become evident that Coronavirus disease 2019 (COVID-19) also affects the central nervous system. This comprehensive review focuses on the neurological manifestations of COVID-19 and its impact on patients with preexisting neurological disorders, particularly those with multiple sclerosis (MS) receiving disease-modifying therapies. Advancements in management, including vaccinations, antiviral therapy, and targeted prophylaxis, have led to a decline in the incidence and severity of COVID-19. Nevertheless, significant complications persist, particularly in patients with advanced MS, who are highly vulnerable to infectious agents like SARS-CoV-2. This review explores the evolving understanding of MS and its association with SARS-CoV-2, encompassing neuroinvasiveness, pathogenesis, disease severity, and outcomes. Research findings reveal substantial neurological implications for some MS patients with COVID-19, with a potential risk of disease relapse and severity. A notable proportion of MS patients experiencing COVID-19 may manifest new symptoms, experience exacerbation of existing symptoms, or encounter both simultaneously, underscoring the diverse neurological effects of the virus. While vaccination and therapeutics have mitigated the overall impact, specific subgroups, especially those on anti-CD20 therapy and with existing disability, remain at higher risk, necessitating ongoing vigilance and tailored care.

IntroductionExtracellular vesicles (EVs) released by human-induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs) have robust antiinflammatory and neurogenic properties due to therapeutic miRNAs and proteins in their cargo. Hence, hiPSC-NSC-EVs are potentially an excellent biologic for treating neurodegenerative disorders, including Alzheimer’s disease (AD).MethodsThis study investigated whether intranasally (IN) administered hiPSC-NSC-EVs would quickly target various neural cell types in the forebrain, midbrain, and hindbrain regions of 3-month-old 5xFAD mice, a model of β-amyloidosis and familial AD. We administered a single dose of 25 × 109 hiPSC-NSC-EVs labeled with PKH26, and different cohorts of naïve and 5xFAD mice receiving EVs were euthanized at 45 min or 6 h post-administration.ResultsAt 45 min post-administration, EVs were found in virtually all subregions of the forebrain, midbrain, and hindbrain of naïve and 5xFAD mice, with predominant targeting and internalization into neurons, interneurons, and microglia, including plaque-associated microglia in 5xFAD mice. EVs also came in contact with the plasma membranes of astrocytic processes and the soma of oligodendrocytes in white matter regions. Evaluation of CD63/CD81 expression with the neuronal marker confirmed that PKH26 + particles found within neurons were IN administered hiPSC-NSC-EVs. At 6 h post-administration, EVs persisted in all cell types in both groups, with the distribution mostly matching what was observed at 45 min post-administration. Area fraction (AF) analysis revealed that, in both naïve and 5xFAD mice, higher fractions of EVs incorporate into forebrain regions at both time points. However, at 45 min post-IN administration, AFs of EVs within cell layers in forebrain regions and within microglia in midbrain and hindbrain regions were lower in 5xFAD mice than naïve mice, implying that amyloidosis reduces EV penetrance.DiscussionCollectively, the results provide novel evidence that IN administration of therapeutic hiPSC-NSC-EVs is an efficient avenue for directing such EVs into neurons and glia in all brain regions in the early stage of amyloidosis. As pathological changes in AD are observed in multiple brain areas, the ability to deliver therapeutic EVs into various neural cells in virtually every brain region in the early stage of amyloidosis is attractive for promoting neuroprotective and antiinflammatory effects.

In December 2019, a new severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) was first reported in China. It would quickly spread and emerge as a COVID-19 pandemic. The illness caused by SARS CoV-2 would fall on a clinical spectrum ranging from asymptomatic, mild to severe respiratory symptoms, ARDS, and death. This led to significant morbidity and mortality further impacting at-risk populations with severe complications. Thus, a concerted worldwide effort to meet the challenges of diagnosing, treating, and preventing COVID-19 led to rapid advances in medicine. Some mitigating methods of masking, social distancing, and frequent handwashing, helped to slow the spread of SARS-CoV-2. Effective therapeutics consisting of antivirals and monoclonal antibodies, plus their use for prophylaxis, contributed to the management of COVID-19. The vaccines from various platforms (mRNA, viral vectors, protein base, and inactivated) contributed to decreased incidence, severity, and overall decreased hospitalizations and mortality. This article aims to review the novel mRNA vaccines (Moderna + Pfizer/BioNTech), viral vector (Janssen& Johnson), and protein base (Novavax), their side effects, and their use as boosters.