Alzheimer’s

INTRODUCTION: In this study, we explore the role of oxidative stress produced by NOX2-containing NADPH oxidase as a molecular mechanism causing capillary stalling and cerebral blood flow deficits in the APP/PS1 mouse model of AD. METHODS: We inhibited NOX2 in APP/PS1 mice by administering a 10 mg/kg dose of the peptide inhibitor gp91-ds-tat i.p., for two weeks. We used in vivo two-photon imaging to measure capillary stalling, penetrating arteriole flow, and vascular inflammation...

BACKGROUND: Genetic and experimental evidence strongly implicates myeloid cells in the etiology of AD and suggests that AD-associated alleles and genes may modulate disease risk by altering the transcriptional and cellular responses of macrophages (like microglia) to damage of lipid-rich tissues (like the brain). Specifically, recent single-cell/nucleus RNA sequencing (sc/nRNA-seq) studies identified a transcriptionally distinct state of subsets of macrophages in aging or degenerating brains (usually referred to as disease- associated microglia or DAM) and in other diseased lipid-rich tissues (e...

Dimension reduction tools preserving similarity and graph structure such as t -SNE and UMAP can capture complex biological patterns in high-dimensional data. However, these tools typically are not designed to separate effects of interest from unwanted effects due to confounders. We introduce the partial embedding (PARE) framework, which enables removal of confounders from any distance-based dimension reduction method. We then develop partial t -SNE and partial UMAP and apply these methods to genomic and neuroimaging data...

Genome-wide association studies (GWAS) provide a powerful means to identify loci and genes contributing to disease, but in many cases the related cell types/states through which genes confer disease risk remain unknown. Deciphering such relationships is important for identifying pathogenic processes and developing therapeutics. Here, we introduce sc-linker, a framework for integrating single-cell RNA-seq (scRNA-seq), epigenomic maps and GWAS summary statistics to infer the underlying cell types and processes by which genetic variants influence disease...

COVID-19 prematurely ended many lives, particularly among the oldest Americans, but the pandemic also had an indirect effect on health and non-COVID mortality among the working-age population, who suffered the brunt of the economic consequences. This analysis investigates whether monthly excess mortality in the US during 2020 varied by age and cause of death. The data comprise national-level monthly death counts by age group and selected causes of death for 1999-2020 combined with annual mid-year population estimates over the same period...

Amyloid protein aggregates are pathological hallmarks of neurodegenerative disorders such as Alzheimer's (AD) and Parkinson's (PD) diseases and are believed to be formed well before the onset of neurodegeneration and cognitive impairment. Monitoring the course of protein aggregation is thus vital to understanding and combating these diseases. We have recently demonstrated that a novel class of fluorescence sensors, oligomeric p -phenylene ethynylene (PE)-based electrolytes (OPEs) selectively bind to and detect prefibrillar and fibrillar aggregates of AD-related amyloid-β (Aβ) peptides over monomeric Aβ...

SCOPE: Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) related imbalance, Tau-hyperphosphorylation, and neuroinflammation, in which Aβ and neuroinflammation can induce brain insulin resistance (IR). Gut microbiome disorder is correlated with inflammation in AD. As of yet, there are no effective treatments clinically. Thus, it is focused on the potential benefit of quercetin-3-O-glucuronide (Q3G), a pharmacologically active flavonol glucuronide, on AD treatment by regulating brain IR and the gut microbiome...

Few studies have evaluated the relationship between in vivo18F-flortaucipir PET and post-mortem pathology. We sought to compare antemortem 18F-flortaucipir PET to neuropathology in a consecutive series of patients with a broad spectrum of neurodegenerative conditions. Twenty patients were included [mean age at PET 61 years (range 34-76); eight female; median PET-to-autopsy interval of 30 months (range 4-59 months)]. Eight patients had primary Alzheimer's disease pathology, nine had non-Alzheimer tauopathies (progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, and frontotemporal lobar degeneration with MAPT mutations), and three had non-tau frontotemporal lobar degeneration...

BACKGROUND: Oxysterols, which are derivatives of cholesterol produced by enzymic or non-enzymic pathways, are potent regulators of cellular lipid homeostasis. Sterol homeostasis in the brain is an important area of interest with regards to neurodegenerative conditions like Alzheimer's disease (AD). Brain cells including neurons and astrocytes express sterol transporters belonging to the ABC transporter family of proteins, including ABCA1, ABCG1 and ABCG4, and these transporters are considered of interest as therapeutic targets...

BACKGROUND AND PURPOSE: Activation of type 2 imidazoline receptors has been shown to exhibit neuroprotective properties including anti-apoptotic and anti-inflammatory effects, suggesting a potential therapeutic value in Alzheimer's disease (AD). Here, we explored the effects of the imidazoline-2 ligand BU224 in a model of amyloidosis. EXPERIMENTAL APPROACH: Six-month-old female transgenic 5XFAD and wild-type (WT) mice were treated intraperitoneally with 5-mg·kg-1 BU224 or vehicle twice a day for 10 days...

BACKGROUND AND OBJECTIVES: The meaning of Alzheimer's disease (AD) is changing in research. It now refers to a pathophysiological process, regardless of whether clinical symptoms are present. In the lay literature, on the other hand, AD is understood as a form of dementia. This raises the question of whether researchers and the lay audience are still talking about the same thing. If not, how will these different understandings of AD shape perspectives on (societal) needs for people with AD? RESEARCH DESIGN AND METHODS: We use framing analysis to retrieve the understandings of the term AD that are upheld in the research literature and in national Dutch newspaper articles...

INTRODUCTION: Subjective cognitive decline (SCD) is a risk condition for dementia, including dementia of Alzheimer type (DAT). METHODS: We report sensitivity, specificity, positive and negative predictive values (PPV, NPV) for conversion to all-cause dementia, and DAT in different SCD types (decline in memory, assocated worries, longitudinal consitency, of the AgeCoDe study (n = 2.402, 12 years follow-up). RESULTS: 82.7% of those converting to any dementia and 84...

Alzheimer's disease (AD) and diabetes mellitus (DM) share common pathophysiological findings, in particular, the mammalian target of rapamycin (mTOR) has been strongly implied to link to AD, while it also plays a key role in the insulin signaling pathway. However, the mechanism of how DM and AD is coupled remains elusive. In the present study, we found that streptozotocin (STZ)-induced DM mice significantly increased the levels P-mTOR Ser2448, P-p70S6K Thr389, P-tau Ser356 and Aβ levels (Aβ oligomer/monomer), as well as the levels of Drp1 and p-Drp1 S616 (mitochondrial fission proteins) are increased, whereas no change was found in the expression of Opa1, Mfn1 and Mfn2 (mitochondrial fusion proteins) compared with control mice...

Alzheimer's disease (AD) is one of the most common neurodegeneration diseases caused by multiple factors. The mechanistic insight of AD remains limited. To disclose molecular mechanisms of AD, many studies have been proposed from transcriptome analyses. However, no analysis across multiple levels of transcription has been conducted to discover co-expression networks of AD. We performed gene-level and isoform-level analyses of RNA sequencing (RNA-seq) data from 544 brain tissues of AD patients, mild cognitive impaired (MCI) patients, and healthy controls...

BACKGROUND: As many countries seek to slow the spread of COVID-19 without reimposing national restrictions, it has become important to track the disease at a local level to identify areas in need of targeted intervention. METHODS: We performed modelling on longitudinal, self-reported data from users of the COVID Symptom Study app in England between 24 March and 29 September, 2020. Combining a symptom-based predictive model for COVID-19 positivity and RT-PCR tests provided by the Department of Health we were able to estimate disease incidence, prevalence and effective reproduction number...

By combining genomic data and brain imaging data, a recent study has identified a novel gene named FAM222A that participates in the formation of amyloid-β (Aβ) plaques and brain atrophy in Alzheimer's disease (AD). FAM222A encodes a 47-kDa protein designated Aggregatin that accumulates in the center of amyloid plaques and physically interacts with Aβ to facilitate Aβ aggregation. Aggregatin is expressed predominantly in the central nervous system (CNS) and its levels are increased in brains of the patients with AD and in mouse models of AD...

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APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer's disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids...

Tauopathies including Alzheimer's disease (AD) are marked by the accumulation of aberrantly modified tau proteins. Acetylated tau, in particular, has recently been implicated in neurodegeneration and cognitive decline. HDAC6 reversibly regulates tau acetylation, but its role in tauopathy progression remains unclear. Here, we identified an HDAC6-chaperone complex that targets aberrantly modified tau. HDAC6 not only deacetylates tau but also suppresses tau hyperphosphorylation within the microtubule-binding region...

Tauopathies are a class of neurodegenerative diseases associated with pathological tau. Despite many advances in our understanding of these diseases, the direct mechanism through which tau contributes to neurodegeneration remains poorly understood. Previously, our laboratory implicated the histone demethylase LSD1 in tau-induced neurodegeneration by showing that LSD1 localizes to pathological tau aggregates in Alzheimer's disease cases, and that it is continuously required for the survival of hippocampal and cortical neurons in mice...