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Upstream transcription factor 1 (USF1) polymorphisms associate with Alzheimer's disease-related neuropathological lesions: Tampere Autopsy Study.

ABSTRACT: The apolipoprotein E (APOE) gene associates with Alzheimer's disease (AD) and cholesterol levels. Upstream transcription factor 1 (USF1) regulates lipid metabolism genes, including APOE, and the AD Aβ-precursor protein. We investigated associations between 6 haplotype-tagging USF1 single-nucleotide polymorphisms (and haplotypes) and AD-related neuropathological lesions [senile plaques (SP), neurofibrillary tangles (NFT) ] in an autopsy series comprising 603 cases (ages 0-97, mean 62 years, 215 women) that died out-of-hospital. In age- and APOE-adjusted analyses, the minor G-allele of rs2774276, previously linked to elevated cholesterol, associated with late-stage burnt out SP among women and early non-neuritic SP among men. The G-allele of the previously unreported rs10908821 showed significant risk of having SP, especially neuritic and burnt out SP, among women but not men. USF1 haplotype GCGCAC carriers (risk alleles of rs2774276 and rs10908821) associated with SP risk, especially neuritic and late-stage burnt out SP, among women but not men. Younger CCGCAC carriers (risk allele of rs2774276 and protective of rs10908821) were more likely to have non-neuritic and diffuse SP. Conversely, USF1 CCGCAC haplotype carriers had lower NFT prevalence among 65+ year-olds. These results suggest USF1 has an independent but gender- and age-associated effect on AD-related brain lesion development.

SUBMITTER: Isotalo K

PROVIDER: S-EPMC8057645 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Upstream Transcription Factor 1 (USF1) allelic variants regulate lipoprotein metabolism in women and USF1 expression in atherosclerotic plaque.

Project description:Upstream transcription factor 1 (USF1) allelic variants significantly influence future risk of cardiovascular disease and overall mortality in females. We investigated sex-specific effects of USF1 gene allelic variants on serum indices of lipoprotein metabolism, early markers of asymptomatic atherosclerosis and their changes during six years of follow-up. In addition, we investigated the cis-regulatory role of these USF1 variants in artery wall tissues in Caucasians. In the Cardiovascular Risk in Young Finns Study, 1,608 participants (56% women, aged 31.9 ± 4.9) with lipids and cIMT data were included. For functional study, whole genome mRNA expression profiling was performed in 91 histologically classified atherosclerotic samples. In females, serum total, LDL cholesterol and apoB levels increased gradually according to USF1 rs2516839 genotypes TT < CT < CC and rs1556259 AA < AG < GG as well as according to USF1 H3 (GCCCGG) copy number 0 < 1 < 2. Furthermore, the carriers of minor alleles of rs2516839 (C) and rs1556259 (G) of USF1 gene had decreased USF1 expression in atherosclerotic plaques (P = 0.028 and 0.08, respectively) as compared to non-carriers. The genetic variation in USF1 influence USF1 transcript expression in advanced atherosclerosis and regulates levels and metabolism of circulating apoB and apoB-containing lipoprotein particles in sex-dependent manner, but is not a major determinant of early markers of atherosclerosis.

| S-EPMC3983598 | biostudies-literature

Neuropathological lesions in the very old: results from a large Brazilian autopsy study.

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| S-EPMC6742578 | biostudies-literature

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| S-EPMC7160616 | biostudies-literature

Upstream stimulatory factors, USF1 and USF2, bind to the human haem oxygenase-1 proximal promoter in vivo and regulate its transcription.

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| S-EPMC1134061 | biostudies-literature

Neuropathological correlates of parkinsonian disorders in a large Dutch autopsy series.

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| S-EPMC7098103 | biostudies-literature

Pro-opiomelanocortin and its Processing Enzymes Associate with Plaque Stability in Human Atherosclerosis - Tampere Vascular Study.

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| S-EPMC6180013 | biostudies-literature

The neuropathological diagnosis of Alzheimer's disease.

Project description:Alzheimer's disease is a progressive neurodegenerative disease most often associated with memory deficits and cognitive decline, although less common clinical presentations are increasingly recognized. The cardinal pathological features of the disease have been known for more than one hundred years, and today the presence of these amyloid plaques and neurofibrillary tangles are still required for a pathological diagnosis. Alzheimer's disease is the most common cause of dementia globally. There remain no effective treatment options for the great majority of patients, and the primary causes of the disease are unknown except in a small number of familial cases driven by genetic mutations. Confounding efforts to develop effective diagnostic tools and disease-modifying therapies is the realization that Alzheimer's disease is a mixed proteinopathy (amyloid and tau) frequently associated with other age-related processes such as cerebrovascular disease and Lewy body disease. Defining the relationships between and interdependence of various co-pathologies remains an active area of investigation. This review outlines etiologically-linked pathologic features of Alzheimer's disease, as well as those that are inevitable findings of uncertain significance, such as granulovacuolar degeneration and Hirano bodies. Other disease processes that are frequent, but not inevitable, are also discussed, including pathologic processes that can clinically mimic Alzheimer's disease. These include cerebrovascular disease, Lewy body disease, TDP-43 proteinopathies and argyrophilic grain disease. The purpose of this review is to provide an overview of Alzheimer's disease pathology, its defining pathologic substrates and the related pathologies that can affect diagnosis and treatment.

| S-EPMC6679484 | biostudies-literature

Argyrophilic Grain Disease: Demographics, Clinical, and Neuropathological Features From a Large Autopsy Study.

Project description:Argyrophilic grain disease (AGD) is a frequent late-onset, 4-repeat tauopathy reported in Caucasians with high educational attainment. Little is known about AGD in non-Caucasians or in those with low educational attainment. We describe AGD demographics, clinical, and neuropathological features in a multiethnic cohort of 983 subjects ?50 years of age from São Paulo, Brazil. Clinical data were collected through semistructured interviews with an informant and included in the Informant Questionnaire on Cognitive Decline in the Elderly, the Clinical Dementia Rating, and the Neuropsychiatric Inventory. Neuropathologic assessment relied on internationally accepted criteria. AGD was frequent (15.2%) and was the only neuropathological diagnosis in 8.9% of all cases (mean, 78.9 ± 9.4 years); it rarely occurred as an isolated neuropathological finding. AGD was associated with older age, lower socioeconomic status (SES), and appetite disorders. This is the first study of demographic, clinical, and neuropathological aspects of AGD in different ethnicities and subjects from all socioeconomic strata. The results suggest that prospective studies of AGD patients include levels of hormones related to appetite control as possible antemortem markers. Moreover, understanding the mechanisms behind higher susceptibility to AGD of low SES subjects may disclose novel environmental risk factors for AGD and other neurodegenerative diseases.

| S-EPMC4913431 | biostudies-literature

Neuropathological Mechanisms Associated with Pesticides in Alzheimer's Disease.

Project description:Environmental toxicants have been implicated in neurodegenerative diseases, and pesticide exposure is a suspected environmental risk factor for Alzheimer's disease (AD). Several epidemiological analyses have affirmed a link between pesticides and incidence of sporadic AD. Meanwhile, in vitro and animal models of AD have shed light on potential neuropathological mechanisms. In this paper, a perspective on neuropathological mechanisms underlying pesticides' induction of AD is provided. Proposed mechanisms range from generic oxidative stress induction in neurons to more AD-specific processes involving amyloid-beta (A?) and hyperphosphorylated tau (p-tau). Mechanisms that are more speculative or indirect in nature, including somatic mutation, epigenetic modulation, impairment of adult neurogenesis, and microbiota dysbiosis, are also discussed. Chronic toxicity mechanisms of environmental pesticide exposure crosstalks in complex ways and could potentially be mutually enhancing, thus making the deciphering of simplistic causal relationships difficult.

| S-EPMC7355712 | biostudies-literature

Longitudinal cognitive performance of Alzheimer's disease neuropathological subtypes.

Project description:IntroductionAlzheimer's disease (AD) neuropathological subtypes (limbic predominant [lpAD], hippocampal sparing [HpSpAD], and typical [tAD]), defined by relative neurofibrillary tangle (NFT) burden in limbic and cortical regions, have not been studied in prospectively characterized epidemiological cohorts with robust cognitive assessments.MethodsTwo hundred ninety-two participants with neuropathologically confirmed AD from the Religious Orders Study and Memory and Aging Project were categorized by neuropathological subtype based on previously specified diagnostic criteria using quantitative regional NFT counts. Rates of cognitive decline were compared across subtypes using linear mixed-effects models that included subtype, time, and a subtype-time interaction as predictors and four cognitive domain factor scores (memory, executive function, language, visuospatial) and a global score as outcomes. To assess if memory was relatively preserved in HpSpAD, non-memory factor scores were included as covariates in the mixed-effects model with memory as the outcome.ResultsThere were 57 (20%) with lpAD, 22 (8%) with HpSpAD and 213 (73%) with tAD. LpAD died significantly later than the participants with tAD (2.4 years, P = .01) and with HpSpAD (3.8 years, P = .03). Compared to tAD, HpSpAD, but not lpAD, performed significantly worse in all cognitive domains at the time of initial impairment and declined significantly faster in memory, language, and globally. HpSpAD did not have relatively preserved memory performance at any time point.ConclusionThe relative frequencies of AD neuropathological subtypes in an epidemiological sample were consistent with a previous report in a convenience sample. People with HpSpAD decline rapidly, but may not have a memory-sparing clinical syndrome. Cohort-specific differences in regional tau burden and comorbid neuropathology may explain the lack of clinicopathological correlation.

| S-EPMC8474122 | biostudies-literature

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