Current Alzheimer Research - Volume 20, Issue 7, 2023

Multiple studies have proposed important roles of T cells in the pathogenesis of Alzheimer's disease. Given the successful application of immune-based therapy for cancer and a variety of diseases, T cell-modifying therapy becomes an attractive way to develop new therapies for Alzheimer's disease and perhaps neurodegenerative diseases in general. However, most of these studies address peripheral T cell responses, while direct pathological evidence documenting T cell infiltration relative to Alzheimer's disease pathological markers (i.e., amyloid plaque and neurofibrillary tangle) is sparse and at best, very preliminary in both human subjects and relevant animal models. Here, we concisely summarize the available pathological data that directly corresponds to T cell infiltration, critically analyze the current knowledge gaps, and thoughtfully propose several key recommendations for future research.

The Alzheimer's disease (AD) continuum is a unique spectrum of cognitive impairment that typically involves the stages of subjective memory complaints (SMC), mild cognitive impairment (MCI), and AD dementia. Neuropsychiatric symptoms (NPS), such as apathy, anxiety, stress, and depression, are highly common throughout the AD continuum. However, there is a dearth of research on how these NPS vary across the AD continuum, especially SMC. There is also disagreement on the effects of specific NPS on each stage of the AD continuum due to their collinearity with other NPS, cognitive decline, and environmental factors (e.g., stress). In this article, we conduct a novel perspective review of the scientific literature to understand the presence of NPS across the AD continuum. Specifically, we review the effects of apathy, depression, anxiety, and stress in AD, MCI, and SMC. We then build on this knowledge by proposing two theories of NPS' occurrence across the AD continuum. Consequently, we highlight the current landscape, limitations (e.g., differing operationalization), and contentions surrounding the NPS literature. We also outline theories that could clear up contention and inspire future NPS research.

Background: MicroRNA (miR)-125a-3p is reported to play an important role in some central nervous system diseases, such as Alzheimer's disease (AD). However, a study has not been conducted on the mechanism of miR-125a-3p in the pathological process of AD.Methods: First, we assessed the expression of miR-125a-3p in AD cohort. Subsequently, we altered the expressions of miR-125a-3p to assess its role in cell viability, cell apoptosis, amyloid-β (Aβ) metabolism, and synaptic activity. Finally, we identified its potential mechanism underlying AD pathology.Results: This study unveiled the potential function of miR-125a-3p through modulating amyloid precursor protein processing. Additionally, miR-125a-3p influenced cell survival and activated synaptic expression through the modulation of Aβ metabolism in the mitogen-activated protein kinase (MAPK) pathway via fibroblast growth factor receptor 2.Conclusion: Our study indicates that targeting miR-125a-3p may be an applicable therapy for AD in the future. However, more in vitro and in vivo studies with more samples are needed to confirm these results.

Aims: We aimed to investigate the interaction between β-amyloid (Aβ) accumulation and cerebral glucose metabolism, cerebral perfusion, and cerebral structural changes in the Alzheimer's disease (AD) clinical continuum.Background: Utility of positron emission tomography (PET) / magnetic resonance imaging (MRI) hybrid imaging for diagnostic categorization of the AD clinical continuum including subjective cognitive decline (SCD), amnestic mild cognitive impairment (aMCI) and Alzheimer's disease dementia (ADD) has not been fully crystallized.Objective: To evaluate the interaction between Aβ accumulation and cerebral glucose metabolism, cerebral perfusion, and cerebral structural changes such as cortex thickness or cerebral white matter disease burden and to detect the discriminative yields of these imaging modalities in the AD clinical continuum.Methods: Fifty patients (20 women and 30 men; median age: 64 years) with clinical SCD (n=11), aMCI (n=17) and ADD (n=22) underwent PET/MRI with [¹⁸F]-fluoro-D-glucose (FDG) and [¹⁸F]- Flutemetamol in addition to cerebral blood flow (CBF) and quantitative structural imaging along with detailed cognitive assessment.Results: High Aβ deposition (increased temporal [¹⁸F]-Flutemetamol standardized uptake value ratio (SUVr) and centiloid score), low glucose metabolism (decreased temporal lobe and posterior cingulate [¹⁸F]-FDG SUVr), low parietal CBF and right hemispheric cortical thickness were independent predictors of low cognitive test performance.Conclusion: Integrated use of structural, metabolic, molecular (Aβ) and perfusion (CBF) parameters contribute to the discrimination of SCD, aMCI, and ADD.

Aim: In this study, OXYS rats of three ages (1, 3, and 6 months), a proven model of Alzheimer's disease (AD), at various stages of disease progression were used to thoroughly study the effects of amisulpride on behavior and tau protein phosphorylation.Background: With the growing number of patients with AD, the problem of finding a cure is very acute. Neurodegeneration in AD has various causes, one of which is hyperphosphorylation of tau protein.Objective: This study aimed to investigate whether amisulpride would affect pathological tau phosphorylation in AD.Methods: We assessed the influence of chronic administration of amisulpride (3 weeks, 3 mg/kg per day, intraperitoneally)-a 5-HT7 receptor inverse agonist-on behavior and tau hyperphosphorylation in OXYS rats (at ages of 1, 3, and 6 months).Results: Chronic administration of amisulpride dramatically decreased tau phosphorylation in the frontal cortex and hippocampus of 3-month-old OXYS rats. Additionally, in 1- and 3-month-old rats' hippocampi, amisulpride diminished the mRNA level of the Cdk5 gene encoding one of the main tau kinases involved in the 5-HT7 receptor-induced effect on tau phosphorylation.Conclusion: Thus, We found that chronic administration of amisulpride could reduce pathological tau hyperphosphorylation while reducing anxiety. We propose amisulpride to have therapeutic potential against AD and that it can be the most effective in the early stages of the disease.

Background: Along with the problem of population aging, the prevalence of dementia is gradually increasing. Associations between vitamin D deficiency (VDD) and cognitive functions remain unclear.Objectives: We aimed to determine the relationship between VDD and changes in cognitive performance in community-dwelling older adults.Methods: In this longitudinal cohort study, participants aged 137;¥65 years were enrolled in March, 2016. The serum level of 25-hydroxy-vitamin D was analyzed by liquid-chromatography-tandem-- mass-spectrometry at baseline. VDD was defined as less than 20 ng/mL. All participants completed a health status questionnaire. Cognitive functions were evaluated by the Wechsler Adult Intelligence Scale-Revised in China at baseline and each visit. The linear mixed-effects model was utilized to examine the association between baseline VDD and changes in cognitive functions.Results: In total, 866 participants were included in our study, with a mean duration of 3 years. VDD was markedly associated with lower full intelligence quotient (FIQ) (β: -3.355, 95% confidence interval [CI]:-4.165,-2.545), verbal intelligence quotient (VIQ) (β: -3.420, 95%CI: -4.193,-2.647), performance intelligence quotient (PIQ) (β: -2.610, 95%CI: -3.683,-1.537), comprehension (β: -0.630, 95%CI: -1.022,-0.238), information (β: -0.354, 95%CI: -0.699,-0.008), arithmetic (β: -1.065, 95%CI: -1.228,-0.902), digit span (β: -0.370, 95%CI: -0.547,-0.192), vocabulary (β: -0.789, 95%CI: -1.084,-0.493), picture completion (β: -0.391, 95%CI: -0.761,-0.022), block design (β: -0.412, 95%CI: -0.697,-0.127), picture arrangement (β: -0.542, 95%CI: -0.909,-0.174), and object assembly (β: -0.492, 95%CI: -0.818,-0.165) than those with adequacy.Conclusion: A higher frequency of VDD was associated with lower scores of FIQ, VIQ, PIQ and subtests on memory and executive function. Future randomized controlled trials are warranted to further verify the conclusions.

Introduction: The present study has examined microglial and astrocyte activation in association with neuronal degeneration in an animal model using an injection of amyloid-beta peptide Aβ1-42 (Aβ42) plus fibrinogen into rat hippocampus.Methods: The combination of stimuli is suggested as a novel and potent perturbation to induce gliosis and the production of glial-derived neurotoxic factors in an animal model exhibiting a leaky BBB (blood-brain barrier). Specifically, Aβ42 + fibrinogen stimulation elevated levels of COX-2 (cyclooxygenase-2) and iNOS (inducible nitric oxide synthase) with a considerable extent of neuronal loss associated with microglia and astrocyte activation.Results: Treatment of injected rats with the broad spectrum anti-inflammatory agent, minocycline or the iNOS inhibitor, 1400 W inhibited gliosis, reduced levels of COX-2 and iNOS, and demonstrated efficacy for neuroprotection.Conclusion: The findings suggest the utility of combining amyloid beta peptide plus fibrinogen as a potent and understudied neuroinflammatory stimulus for the induction of glial-derived neurotoxic factors in BBB-compromised AD brain.