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Growing evidence has demonstrated that long non-coding RNAs (lncRNAs) play a critical role in Alzheimer's disease (AD), which is characterized by sustained mitochondrial dysfunction, inevitable memory loss, and cognitive decline. However, the potential function of lncRNAs MIR600 Host Gene (MIR600HG) in AD remains unanswered. Our study aimed to investigate the role of MIR600HG and its related molecular mechanism in AD. The expression of MIR600HG was examined by qRT-PCR. The MIR600HG interacting proteins were identified by RNA pull-down assay and mass spectrometry and verified by RNA immunoprecipitation. Immunofluorescence staining was applied to examine the colocalization of PINK1 and NEDD4L. The PINK1 level and the activation of autophagy were detected by immunoblotting. Morris water maze test was performed to evaluate cognitive decline in AD mice model. MIR600HG expression was elevated during aging in two different types of AD transgenic mouse models. Next, we found that increased MIR600HG directly interact with NEDD4L, which promoted PINK1 ubiquitination and degradation, and as well as autophagy activation. Additionally, MIR600HG promoted Aβ production and suppressed Cytochrome C Oxidase activity. Administration of AAV-shMIR600HG restored the Cytochrome C Oxidase activity and inhibited Aβ production. Furthermore, PINK1 overexpression or MIR600HG knockdown significantly ameliorated the cognitive impairment in APP/PS1 mice. PINK1 depletion recovered the spatial memory defect in the AAV-shMIR600HG injected APP/PS1 mice. MIR600HG was increased in AD and promoted AD pathogenesis. Targeting MIR600HG significantly improved cognitive function in AD mice, which could pave the way for exciting new avenues in AD therapeutic strategy research.MIR600HG was increased in AD and promoted AD pathogenesis. Targeting MIR600HG significantly improved cognitive function in AD mice, which could pave the way for exciting new avenues in AD therapeutic strategy research. Life-course approaches to identify and help improve modifiable risk factors, particularly in midlife, may mitigate cognitive aging. We examined how midlife self-rated physical functioning and health may predict cognitive health in older age. We used data from the Health and Retirement Study (1998-2016; unweighted-N = 4,685). We used survey multinomial logistic regression and latent growth curve models to examine how midlife (age 50-64 years) activities of daily living (ADL), physical function, and self-reported health affect cognitive trajectories and cognitive impairment not dementia (CIND) and dementia status 18 years later. Then, we tested for sex and racial/ethnic modifications. After covariates-adjustment, worse instrumental ADL (IADL) functioning, mobility, and self-reported health were associated with both CIND and dementia. Hispanics were more likely to meet criteria for dementia than non-Hispanic Whites given increasing IADL impairment. Midlife health, activities limitations, and difficulties with mobility are predictive of dementia in later life. Hispanics may be more susceptible to dementia in the presence of midlife IADLs. Assessing midlife physical function and general health with brief questionnaires may be useful for predicting cognitive impairment and dementia in later life.Midlife health, activities limitations, and difficulties with mobility are predictive of dementia in later life. Hispanics may be more susceptible to dementia in the presence of midlife IADLs. Assessing midlife physical function and general health with brief questionnaires may be useful for predicting cognitive impairment and dementia in later life. Altered gait is a frequent feature of Alzheimer's disease (AD), as is vitamin D deficiency. Treatment with memantine and vitamin D can protect cortical axons from exposure to amyloid-β and glutamate toxicity, suggesting this combination may mitigate altered gait in AD. Investigate the effects of vitamin D deprivation and subsequent treatment with memantine and vitamin D enrichment on gait performance in APPswe/PS1dE9 mice. Male APPswe/PS1dE9 mice were split into four groups (n = 14 each) at 2.5 months of age. A control group was fed a standard diet throughout while the other three groups started a vitamin D-deficient diet at month 6. One group remained on this deficient diet for the rest of the study. At month 9, the other two groups began treatment with either memantine alone or memantine combined with 10 IU/g of vitamin D. Gait was assessed using CatWalk at months 6, 9, 12, and 15. Vitamin D deprivation led to a 13% increase in hind stride width by month 15 (p < 0.001). Examination of the treatment groups at month 15 revealed that mice treated with memantine alone still showed an increase in hind stride width compared to controls (p < 0.01), while mice treated with memantine and vitamin D did not (p = 0.21). Vitamin D deprivation led to impaired postural control in the APPswe/PS1dE9 model. Treatment with memantine and vitamin D, but not memantine alone, prevented this impairment. Future work should explore the potential for treatments incorporating vitamin D supplementation to improve gait in people with AD.Vitamin D deprivation led to impaired postural control in the APPswe/PS1dE9 model. Treatment with memantine and vitamin D, but not memantine alone, prevented this impairment. Future work should explore the potential for treatments incorporating vitamin D supplementation to improve gait in people with AD. Tauopathy is a primary neuropathological hallmark of Alzheimer's disease with a strong relationship to cognitive impairment. In the brain, tau aggregation is associated with the regulation of tau kinases and the binding ability of tau to microtubules. To explore the potential for using specific polygenic risk scores (PRSs), combining the genetic influences involved in tau-protein kinases and the tau-protein binding pathway, as predictors of tau pathology and cognitive decline in non-demented individuals. We computed a pathway-specific PRS using summary statistics from previous large-scale genome-wide association studies of dementia. We examined whether PRS is related to tau uptake in positron emission tomography (PET), tau levels, and the rate of tau level changes in cerebrospinal fluid (CSF). We further assessed whether PRS is associated with memory impairment mediated by CSF tau levels. A higher PRS was related to elevated CSF tau levels and tau-PET uptake at baseline, as well as greater rates of change in CSF tau levels. Moreover, PRS was associated with memory impairment, mediated by increased CSF tau levels. The association between PRS and tau pathology was significant when APOE was excluded, even among females. However, the effect of PRS on cognitive decline appeared to be driven by the inclusion of APOE. The influence of genetic risk in a specific tau-related biological pathway may make an individual more susceptible to tau pathology, resulting in cognitive dysfunction in an early preclinical phase of the disease.The influence of genetic risk in a specific tau-related biological pathway may make an individual more susceptible to tau pathology, resulting in cognitive dysfunction in an early preclinical phase of the disease. Alzheimer's disease (AD) is a progressive age-dependent disorder whose risk is affected by genetic factors. Better models for investigating early effects of risk factors such as apolipoprotein E (APOE) genotype are needed. To determine whether APOE genotype produces neuropathologies in an AD-susceptible neural system, we compared effects of human APOE ɛ3 (E3) and APOE ɛ4 (E4) alleles on the mouse olfactory epithelium. RNA-Seq using the STAR aligner and DESeq2, immunohistochemistry for activated caspase-3 and phosphorylated histone H3, glucose uptake after oral gavage of 2-[1,2-3H (N)]-deoxy-D-glucose, and Seahorse Mito Stress tests on dissociated olfactory mucosal cells. E3 and E4 olfactory mucosae show 121 differentially abundant mRNAs at age 6 months. These do not indicate differences in cell type proportions, but effects on 17 odorant receptor mRNAs suggest small differences in tissue development. Ten oxidoreductases mRNAs important for cellular metabolism and mitochondria are less abundant in E4 olfactory mucosae but this does not translate into differences in cellular respiration. E4 olfactory mucosae show lower glucose uptake, characteristic of AD susceptibility and consistent with greater expression of the glucose-sensitive gene, Asns. Olfactory sensory neuron apoptosis is unaffected at age 6 months but is greater in E4 mice at 10 months. Effects of human APOE alleles on mouse olfactory epithelium phenotype are apparent in early adulthood, and neuronal loss begins to increase by middle age (10 months). The olfactory epithelium is an appropriate model for the ability of human APOE alleles to modulate age-dependent effects associated with the progression of AD.Effects of human APOE alleles on mouse olfactory epithelium phenotype are apparent in early adulthood, and neuronal loss begins to increase by middle age (10 months). https://www.selleckchem.com/products/protoporphyrin-ix.html The olfactory epithelium is an appropriate model for the ability of human APOE alleles to modulate age-dependent effects associated with the progression of AD. Alzheimer's disease (AD) and normal pressure hydrocephalus (NPH) commonly coexist. We aimed to characterize an overlapping syndrome of AD and NPH that presents with gait disturbance, ventriculomegaly on magnetic resonance imaging, and significant amyloid deposition on positron emission tomography (PET). Of 114 patients who underwent cerebrospinal fluid (CSF) drainage for a possible diagnosis of NPH between 2015 and 2020 in Samsung Medical Center, we identified 24 patients (21.1%) with the NPH patients with amyloid deposition on PET, which we referred to as hydrocephalic AD in this study. We compared their clinical and imaging findings with those of 123 typical AD without hydrocephalic signs/symptoms. We also investigated the frequency and potential predictors of the tap test response in hydrocephalic AD. Evans' index was 0.36±0.03, and a disproportionately enlarged subarachnoid space was present in 54.2% of the hydrocephalic AD patients. The mean age (75.2±7.3 years) and the APOE4 frequency (68.2%) did not differ from those of AD controls. However, the hydrocephalic AD patients showed better memory and language performance, and a thinner cingulate cortex. About 42% of the hydrocephalic AD patients responded to the tap test, of whom seven underwent shunt surgery. Cognition did not improve, whereas gait improved after shunt surgery in all. Hydrocephalic AD has different neuropsychological and imaging characteristics from typical AD. Future studies are warranted to further investigate the effect of CSF removal on their clinical course and to elucidate the pathophysiological interaction between amyloid and NPH.Hydrocephalic AD has different neuropsychological and imaging characteristics from typical AD. Future studies are warranted to further investigate the effect of CSF removal on their clinical course and to elucidate the pathophysiological interaction between amyloid and NPH.
