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Frontiers in Immunology 2023A complex network of interactions exists between the olfactory, immune and central nervous systems. In this work we intend to investigate this connection through the use...
Improvement of cognitive function in wild-type and Alzheimer´s disease mouse models by the immunomodulatory properties of menthol inhalation or by depletion of T regulatory cells.
A complex network of interactions exists between the olfactory, immune and central nervous systems. In this work we intend to investigate this connection through the use of an immunostimulatory odorant like menthol, analyzing its impact on the immune system and the cognitive capacity in healthy and Alzheimer's Disease Mouse Models. We first found that repeated short exposures to menthol odor enhanced the immune response against ovalbumin immunization. Menthol inhalation also improved the cognitive capacity of immunocompetent mice but not in immunodeficient NSG mice, which exhibited very poor fear-conditioning. This improvement was associated with a downregulation of IL-1β and IL-6 mRNA in the brain´s prefrontal cortex, and it was impaired by anosmia induction with methimazole. Exposure to menthol for 6 months (1 week per month) prevented the cognitive impairment observed in the APP/PS1 mouse model of Alzheimer. Besides, this improvement was also observed by the depletion or inhibition of T regulatory cells. Treg depletion also improved the cognitive capacity of the APP Alzheimer´s mouse model. In all cases, the improvement in learning capacity was associated with a downregulation of IL-1β mRNA. Blockade of the IL-1 receptor with anakinra resulted in a significant increase in cognitive capacity in healthy mice as well as in the APP/PS1 model of Alzheimer´s disease. These data suggest an association between the immunomodulatory capacity of smells and their impact on the cognitive functions of the animals, highlighting the potential of odors and immune modulators as therapeutic agents for CNS-related diseases.
Topics: Mice; Animals; Alzheimer Disease; Menthol; Amyloid beta-Protein Precursor; T-Lymphocytes, Regulatory; Mice, Transgenic; Cognition; Immunity
PubMed: 37187754
DOI: 10.3389/fimmu.2023.1130044 -
Journal of Alzheimer's Disease : JAD 2023Deterioration of the oral environment is one of the risk factors for dementia. A previous study of an Alzheimer's disease (AD) model mouse suggests that tooth loss...
BACKGROUND
Deterioration of the oral environment is one of the risk factors for dementia. A previous study of an Alzheimer's disease (AD) model mouse suggests that tooth loss induces denervation of the mesencephalic trigeminal nucleus and neuroinflammation, possibly leading to accelerated tau dissemination from the nearby locus coeruleus (LC).
OBJECTIVE
To elucidate the relevance of oral conditions and amyloid-β (Aβ) and tau pathologies in human participants.
METHODS
We examined the number of remaining teeth and the biofilm-gingival interface index in 24 AD-spectrum patients and 19 age-matched healthy controls (HCs). They also underwent positron emission tomography (PET) imaging of Aβ and tau with specific radiotracers, 11C-PiB and 18F-PM-PBB3, respectively. All AD-spectrum patients were Aβ-positive, and all HCs were Aβ-negative. We analyzed the correlation between the oral parameters and radiotracer retention.
RESULTS
No differences were found in oral conditions between the AD and HC groups. 11C-PiB retentions did not correlate with the oral indices in either group. In AD-spectrum patients, brain-wide, voxel-based image analysis highlighted several regions, including the LC and associated brainstem substructures, as areas where 18F-PM-PBB3 retentions negatively correlated with the remaining teeth and revealed the correlation of tau deposits in the LC (r = -0.479, p = 0.018) primarily with the hippocampal and neighboring areas. The tau deposition in none of the brain regions was associated with the periodontal status.
CONCLUSIONS
Our findings with previous preclinical evidence imply that tooth loss may enhance AD tau pathogenesis, promoting tau spreading from LC to the hippocampal formation.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Positron-Emission Tomography; tau Proteins; Tooth Loss
PubMed: 37980663
DOI: 10.3233/JAD-230581 -
Journal of Alzheimer's Disease : JAD 2020One of the challenges in translating new therapeutic approaches to the patient bedside lies in bridging the gap between scientists who are conducting basic laboratory... (Review)
Review
One of the challenges in translating new therapeutic approaches to the patient bedside lies in bridging the gap between scientists who are conducting basic laboratory research and medical practitioners who are not exposed to highly specialized journals. This review covers the literature on photobiomodulation therapy as a novel approach to prevent and treat Alzheimer's disease, aiming to bridge that gap by gathering together the terms and technical specifications into a single concise suggestion for a treatment protocol. In light of the predicted doubling in the number of people affected by dementia and Alzheimer's disease within the next 30 years, a treatment option which has already shown promising results in cell culture studies and animal models, and whose safety has already been proven in humans, must not be left in the dark. This review covers the mechanistic action of photobiomodulation therapy against Alzheimer's disease at a cellular level. Safe and effective doses have been found in animal models, and the first human case studies have provided reasons to undertake large-scale clinical trials. A brief discussion of the minimally effective and maximum tolerated dose concludes this review, and provides the basis for a successful translation from bench to bedside.
Topics: Alzheimer Disease; Animals; Brain; Disease Models, Animal; Humans; Phototherapy; Translational Research, Biomedical
PubMed: 32390621
DOI: 10.3233/JAD-191210 -
Stem Cell Research & Therapy May 2024Alzheimer's disease (AD) is a prevalent form of dementia leading to memory loss, reduced cognitive and linguistic abilities, and decreased self-care. Current AD... (Review)
Review
BACKGROUND
Alzheimer's disease (AD) is a prevalent form of dementia leading to memory loss, reduced cognitive and linguistic abilities, and decreased self-care. Current AD treatments aim to relieve symptoms and slow disease progression, but a cure is elusive due to limited understanding of the underlying disease mechanisms.
MAIN CONTENT
Stem cell technology has the potential to revolutionize AD research. With the ability to self-renew and differentiate into various cell types, stem cells are valuable tools for disease modeling, drug screening, and cell therapy. Recent advances have broadened our understanding beyond the deposition of amyloidβ (Aβ) or tau proteins in AD to encompass risk genes, immune system disorders, and neuron-glia mis-communication, relying heavily on stem cell-derived disease models. These stem cell-based models (e.g., organoids and microfluidic chips) simulate in vivo pathological processes with extraordinary spatial and temporal resolution. Stem cell technologies have the potential to alleviate AD pathology through various pathways, including immunomodulation, replacement of damaged neurons, and neurotrophic support. In recent years, transplantation of glial cells like oligodendrocytes and the infusion of exosomes have become hot research topics.
CONCLUSION
Although stem cell-based models and therapies for AD face several challenges, such as extended culture time and low differentiation efficiency, they still show considerable potential for AD treatment and are likely to become preferred tools for AD research.
Topics: Alzheimer Disease; Humans; Stem Cell Transplantation; Animals; Stem Cells
PubMed: 38715083
DOI: 10.1186/s13287-024-03737-w -
Journal of Neural Transmission (Vienna,... Jul 2022Individuals with Alzheimer's disease and other neurodegenerative diseases have been exposed to excess risk by the COVID-19 pandemic. COVID-19's main manifestations... (Review)
Review
Individuals with Alzheimer's disease and other neurodegenerative diseases have been exposed to excess risk by the COVID-19 pandemic. COVID-19's main manifestations include high body temperature, dry cough, and exhaustion. Nevertheless, some affected individuals may have an atypical presentation at diagnosis but suffer neurological signs and symptoms as the first disease manifestation. These findings collectively show the neurotropic nature of SARS-CoV-2 virus and its ability to involve the central nervous system. In addition, Alzheimer's disease and COVID-19 has a number of common risk factors and comorbid conditions including age, sex, hypertension, diabetes, and the expression of APOE ε4. Until now, a plethora of studies have examined the COVID-19 disease but only a few studies has yet examined the relationship of COVID-19 and Alzheimer's disease as risk factors of each other. This review emphasizes the recently published evidence on the role of the genes of early- or late-onset Alzheimer's disease in the susceptibility of individuals currently suffering or recovered from COVID-19 to Alzheimer's disease or in the susceptibility of individuals at risk of or with Alzheimer's disease to COVID-19 or increased COVID-19 severity and mortality. Furthermore, the present review also draws attention to other uninvestigated early- and late-onset Alzheimer's disease genes to elucidate the relationship between this multifactorial disease and COVID-19.
Topics: Alzheimer Disease; COVID-19; Humans; Pandemics; Risk Factors; SARS-CoV-2
PubMed: 35429259
DOI: 10.1007/s00702-022-02499-0 -
Pharmacological Reports : PR Dec 2021Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system (CNS) leading to mental deterioration and devastation, and eventually... (Review)
Review
Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system (CNS) leading to mental deterioration and devastation, and eventually a fatal outcome. AD affects mostly the elderly. AD is frequently accompanied by hypercholesterolemia, hypertension, atherosclerosis, and diabetes mellitus, and these are significant risk factors of AD. Other conditions triggered by the progression of AD include psychosis, sleep disorders, epilepsy, and depression. One important comorbidity is Down's syndrome, which directly contributes to the severity and rapid progression of AD. The development of new therapeutic strategies for AD includes the repurposing of drugs currently used for the treatment of comorbidities. A better understanding of the influence of comorbidities on the pathogenesis of AD, and the medications used in its treatment, might allow better control of disease progression, and more effective pharmacotherapy.
Topics: Aged; Alzheimer Disease; Animals; Disease Progression; Drug Development; Drug Repositioning; Humans; Patient Acuity; Risk Factors
PubMed: 34121170
DOI: 10.1007/s43440-021-00293-5 -
Alzheimer's & Dementia : the Journal of... Jun 2023Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to...
INTRODUCTION
Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes.
METHODS
We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808).
RESULTS
Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively.
DISCUSSION
The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets.
Topics: Humans; Alzheimer Disease; Exome; Genetic Association Studies; Phenotype; Biomarkers
PubMed: 36464806
DOI: 10.1002/alz.12842 -
Alzheimer's Research & Therapy Sep 2022The individual and complementary value of the Visual Short-Term Memory Binding Test (VSTMBT) and the Free and Cued Selective Reminding Test (FCSRT) as markers to trace...
BACKGROUND
The individual and complementary value of the Visual Short-Term Memory Binding Test (VSTMBT) and the Free and Cued Selective Reminding Test (FCSRT) as markers to trace the AD continuum was investigated. It was hypothesised that the VSTMBT would be an early indicator while the FCSRT would inform on imminent progression.
METHODS
Healthy older adults (n=70) and patients with mild cognitive impairment (MCI) (n=80) were recruited and followed up between 2012 and 2017. Participants with at least two assessment points entered the study. Using baseline and follow-up assessments four groups were defined: Older adults who were healthy (HOA), with very mild cognitive but not functional impairment (eMCI), and with MCI who did and did not convert to dementia (MCI converters and non-converters).
RESULTS
Only the VSTMBT predicted group membership in the very early stages (HOA vs eMCI). As the disease progressed, the FCSRT became a strong predictor excluding the VSTMB from the models. Their complementary value was high during the mid-prodromal stages and decreased in stages closer to dementia.
DISCUSSION
The study supports the notion that neuropsychological assessment for AD needs to abandon the notion of one-size-fits-all. A memory toolkit for AD needs to consider tools that are early indicators and tools that suggest imminent progression. The VSTMBT and the FSCRT are such tools.
Topics: Aged; Humans; Alzheimer Disease; Aniline Compounds; Biomarkers; Cognitive Dysfunction; Disease Progression; Neuropsychological Tests
PubMed: 36180965
DOI: 10.1186/s13195-022-01082-9 -
Nutrients Jan 2021The microbiota-gut-brain axis plays an important role in the development of neurodegenerative diseases. Commensal and pathogenic enteric bacteria can influence brain and... (Review)
Review
The microbiota-gut-brain axis plays an important role in the development of neurodegenerative diseases. Commensal and pathogenic enteric bacteria can influence brain and immune system function by the production of lipopolysaccharides and amyloid. Dysbiosis of the intestinal microbiome induces local and consecutively systemic immune-mediated inflammation. Proinflammatory cytokines then trigger neuroinflammation and finally neurodegeneration. Immune-mediated oxidative stress can lead to a deficiency of vitamins and essential micronutrients. Furthermore, the wrong composition of gut microbiota might impair the intake and metabolization of nutrients. In patients with Alzheimer's disease (AD) significant alterations of the gut microbiota have been demonstrated. Standard Western diet, infections, decreased physical activity and chronic stress impact the composition and diversity of gut microbiota. A higher abundancy of "pro-inflammatory" gut microbiota goes along with enhanced systemic inflammation and neuroinflammatory processes. Thus, AD beginning in the gut is closely related to the imbalance of gut microbiota. Modulation of gut microbiota by Mediterranean diet, probiotics and curcumin can slow down cognitive decline and alter the gut microbiome significantly. A multi-domain intervention approach addressing underlying causes of AD (inflammation, infections, metabolic alterations like insulin resistance and nutrient deficiency, stress) appears very promising to reduce or even reverse cognitive decline by exerting positive effects on the gut microbiota.
Topics: Aged; Alzheimer Disease; Gastrointestinal Microbiome; Humans
PubMed: 33504065
DOI: 10.3390/nu13020361 -
The Journal of Prevention of... 2023Alzheimer's disease (AD) prevention trials require a large outreach and screening funnel to identify cognitively unimpaired adults who meet the study's inclusion... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Alzheimer's disease (AD) prevention trials require a large outreach and screening funnel to identify cognitively unimpaired adults who meet the study's inclusion criteria, such as certain clinical or demographic criteria, genetic risk factors, and/or biomarker evidence of the disease.
OBJECTIVES
Describe tactics and strategies to identify and enroll cognitively unimpaired adults with one (heterozygotes [HT]) or two (homozygotes [HM]) copies of the APOE ε4 allele, a genetic risk factor for dementia due to AD, into the Alzheimer's Prevention Initiative (API) Generation Program, the largest and only prevention trials for late onset AD using this enrichment technique.
DESIGN AND SETTING
The Generation Program was comprised of two global, randomized, double-blind, placebo-controlled, parallel group adaptive design with variable treatment duration clinical trials. Generation Study 1 randomized participants into one of two cohorts: Cohort 1 which evaluated CAD106 vs. placebo or Cohort 2 which evaluated umibecestat vs placebo. Generation Study 2 randomized participants into two doses of umibecestat vs. placebo. The Generation Program was terminated early in 2019, while enrollment was still occurring.
PARTICIPANTS
Both Generation Study 1 and Generation Study 2 enrolled cognitively unimpaired APOE ε4 HMs aged 60-75; Generation Study 2 also enrolled APOE ε4 HTs ages 60-75 with elevated brain amyloid.
METHODS AND MEASUREMENTS
Describe results of the centralized and localized outreach, recruitment, screening strategies and tactics as well as characteristics of sites successful at enrolling genetically eligible participants, with a particular focus on APOE ε4 HMs given the 2-3% prevalence of this genotype.
RESULTS
At the time the trial program was terminated, 35,333 individuals had consented to the optional prescreening ICF1a/ICFA and provided a sample of DNA for APOE genotyping, 1,138 APOE ε4 HMs consented to screening for Generation Study 1 (ICF1b), and 1,626 APOE ε4 carriers were randomized into either Generation Study 1 or Generation Study 2. Genetic testing registries, partnerships with genetic testing/counseling companies, and the optional prescreening ICF1a/ICFA were the most successful strategies for identifying genetically eligible participants for screening.
CONCLUSIONS
It is feasible to recruit, screen and randomize cognitively unimpaired APOE ε4 carriers, particularly APOE ε4 HMs for a global AD prevention trial. The Generation Program was on track to complete enrollment by end of 2019. Factors that were key to this success included: working with sites to develop customizable outreach, recruitment, and screening programs specific to their site needs, providing forums for sites to exchange best practices, and developing partnerships between the sponsor team and trial sites.
Topics: Adult; Humans; Alzheimer Disease; Heterozygote; Apolipoprotein E4; Random Allocation; Genotype
PubMed: 37357285
DOI: 10.14283/jpad.2023.27