Browsing by Subject "Alzheimer's"

Now showing 1 - 4 of 4
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    Engaging Older Adults with Alzheimer's Disease in Exercise: Impact on Caregivers
    (2022-05) Sims, Tai
    In 2020, over 11 million informal caregivers cared for 6.5 million older adults with Alzheimer’s disease in America. By 2050 the number of older adults with Alzheimer’s disease is projected to double, which will demand the need for more informal caregivers. Family most often serve as informal caregivers. Informal caregiving is associated with increased burden, and poorer wellbeing and overall health. Interventions that target family caregivers of people with Alzheimer’s disease have shown minimal benefit on caregiver outcomes. Interventions that target people with Alzheimer’s disease, often neglect examining the intervention’s impact on family caregivers. In particular, exercise interventions have shown some promise in improving cognition and physical function of people with Alzheimer’s disease; however, little is known on how such interventions impact family caregivers. The purpose of this mixed methods study was to evaluate the impact of a 6 month, moderate intensity aerobic exercise intervention for community-dwelling older adults with Alzheimer’s disease on caregiver burden, wellbeing and general health. The study results were mixed across quantitative and qualitative data for caregiver burden and wellbeing. However, the findings suggest that improved caregiver burden and wellbeing may have been a consequence of perceived benefits of respite time and social support received by both study groups, rather than changes in care-recipients as a result of the exercise intervention. Both quantitative and qualitative data indicated the exercise intervention did not influence caregivers’ general health. This study provides some insight that integrating a family caregiver component into community-based exercise programs has the potential to benefit both people with Alzheimer’s disease and their family caregivers.
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    Gut Microbial Metabolite, Sodium Butyrate Regulates The Blood-Brain Barrier Transport And Intra-Endothelial Accumulation Of Alzheimer’S Disease Amyloid-Beta Peptides
    (2024-01) Veerareddy, Vaishnavi
    Alzheimer's disease (AD) is a common type of dementia observed in the elderly with brain amyloid beta (Aꞵ) deposits as one of its pathological hallmarks. Risk factors contributing to AD include age, genetics, inflammation, gut dysbiosis, and co-morbidities like diabetes, hypertension, and insulin resistance1. Recent studies have highlighted the necessity of investigating the combined effect of risk factors on AD onset and progression2. In addition, a majority of AD patients are diagnosed with cerebrovascular dysfunction, which is considered to be a significant contributor to the disease progression3. Moreover, the gut microbiome diversity was shown to be diminished in AD patients4. One of the interactions between the gut and the brain is mediated by gut microbial metabolites through the gut-brain axis5. Gut microbial metabolites include mainly short-chain fatty acids (acetate, propionate, butyrate) and trimethylamine N-oxide (TMAO)6. Particularly, butyrate treatment was shown to improve impaired cognition and reduce Aꞵ deposition in the AD brain, although the underlying mechanisms are yet to be characterized7. Previously, we reported the impact of insulin signaling on Aꞵ trafficking between the brain and the blood via the blood-brain barrier (BBB), which lines the cerebrovascular lumen and regulates Aꞵ levels in the brain8. However, the effect of gut microbiome metabolites on Aꞵ trafficking/accumulation at the BBB and endothelial insulin signaling remains unknown. In this study, we investigated the effect of one of the bacterial metabolites, sodium butyrate (NaBu), on Aꞵ accumulation at the BBB endothelium and the role of endothelial insulin signaling. The NaBu decreased Aꞵ40 with 6 h treatment and Aꞵ42 accumulation upon 2 h and 6 h treatments in BBB cell (hCMEC/D3) monolayers in vitro. Moreover, NaBu increased the phosphorylation of protein kinase B (PKB/AKT) and extracellular signal-regulated kinase (ERK) upon 6 h treatment. Inhibitor studies were conducted to evaluate if NaBu effect on Aꞵ accumulation at the BBB is regulated by insulin signaling. Treatment with AKT inhibitor (MK2206) and NaBu increased Aꞵ42 accumulation compared to the NaBu alone treated group. Similarly, treatment with MEK inhibitor (trametinib) and NaBu increased Aꞵ42 accumulation compared to the NaBu-treated group. These findings suggest the involvement of AKT and ERK pathways in NaBu-mediated changes in Aꞵ42 accumulation at the BBB. Also, NaBu affects the expression of transporters and receptors at the BBB. The NaBu treatment increased permeability glycoprotein (P-gp) and decreased receptors for advanced glycated end products (RAGE) compared to the Aꞵ treated group. Further, studies need to be conducted to elucidate mechanisms underlying NaBu effect on the BBB endothelium in AD. Keywords: Alzheimer’s, Aβ, Blood-brain barrier, dysbiosis, sodium butyrate, Insulin signaling, P-gp, RAGE.
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    Soluble alpha-synuclein oligomers are associated with reduced synapsin expression and enhanced cognitive decline in Alzheimer's disease
    (2014-02) Greimel, Susan Jean
    We recently proposed that soluble, intraneuronal alpha-synuclein (alpha-Syn) might modulate Alzheimer's disease (AD) pathophysiology in the absence of Lewy body (LB) pathology. With mounting evidence indicating that oligomeric forms of aggregation-prone proteins such as A-beta, tau and alpha-Syn may be the major bioactive deleterious agents involved in AD, frontotemporal dementia and Parkinson's disease, we sought to identify the nature of the soluble alpha-Syn species elevated in AD and to determine the relative contribution of soluble alpha-Syn oligomers to AD-associated cognitive deficits. Using enzyme-linked immunosorbent assays designed to detect oligomeric alpha-Syn in our well-characterized human cohort, we found elevated levels of soluble alpha-Syn oligomers (o-alpha-Syn) in AD brains compared to aged-matched controls in the absence of LB cytopathology. Upon finical measurements of soluble alpha-Syn in subjects with AD, we not only detected 2 forms of monomeric alpha-Syn but also apparent multimers of each monomer. Unexpectedly, only a subset of soluble o-alpha-Syn species was elevated intracellularly while extracellular o-alpha-Syn remained unchanged. Multivariate analyses revealed that the respective abundance of selective low molecular weight o-alpha-Syn was associated with cognitive deficits in multiple domains. Finally, we found that elevating o-alpha-Syn in an AD mouse model triggered a selective decrease in synapsins and exacerbated A-beta-induced cognitive deficits. Altogether, our data support differential roles for soluble, intraneuronal alpha-Syn oligomers in Alzheimer's disease, which could extend to other synucleinopathies.
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    Specific amyloid-beta oligomers in-human cerebrospinal fluid.
    (2012) Handoko, Maureen
    Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a long preclinical stage, during which pathological changes and biomarker abnormalities, such as elevations of tau proteins in the cerebrospinal fluid (CSF), occur in the absence of cognitive impairment. Research on the etiology of AD in cell culture and animals have suggested that soluble oligomers of amyloid-β (Aβ), such as Aβ*56, trimers, and dimers, are the synaptotoxic species in AD and are thought to be responsible for initiating the cognitive impairment associated with the early stages of disease. These studies also suggest that tau pathology develops downstream of Aβ and may mediate the detrimental effects of Aβ on learning and memory. However, the whether these Aβ oligomers exist in humans and are associated with disease processes of AD is still unknown. To address this question, we developed a sensitive method to detect Aβ*56, trimers, and dimers in lumbar CSF, enabling the study of these oligomers in clinically characterized living subjects. Biochemical study of CSF from cognitively intact subjects and impaired subjects with clinical diagnosis of AD and mild cognitive impairment (MCI) showed that these oligomers were present in the CSF of both the unimpaired and impaired subjects.Within the unimpaired group, subjects at a higher risk of having preclinical AD had elevated levels of Aβ oligomers. Furthermore, Aβ*56, dimers, and trimers were positively correlated with total or abnormally phosphorylated tau in the CSF of unimpaired subjects, suggesting that these oligomers are associated with disease processes and may induce tau abnormalities in the preclinical phase of disease. Study of CSF from subjects enrolled in a longitudinal study showed that Aβ*56 was negatively correlated with memory in unimpaired subjects who converted to MCI/AD during follow-up. However, baseline Aβ oligomer levels were not predictive of conversion to MCI/AD from cognitive normality. Further exploratory analysis revealed significant associations between high levels of baseline total tau or low Aβ*56 levels and a faster rate of memory decline. The results of these studies are consistent with the hypothesis that Aβ oligomers may trigger tau abnormalities in preclinical AD, and that Aβ*56 may play a pathological role in preclinical AD but is not sufficient to trigger disease progression. A hypothetical model describing the characteristics of Aβ*56 and tau during the preclinical phase of AD was generated from this data and awaits further evaluation.