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BioRxiv : the Preprint Server For... Jun 2024Proteome changes associated with APOE4 variant carriage that are independent of Alzheimer's disease (AD) pathology and diagnosis are unknown. This study investigated...
INTRODUCTION
Proteome changes associated with APOE4 variant carriage that are independent of Alzheimer's disease (AD) pathology and diagnosis are unknown. This study investigated APOE4 proteome changes in people with AD, mild cognitive impairment, and no impairment.
METHODS
Clinical, APOE genotype, and cerebrospinal fluid (CSF) proteome and AD biomarker data was sourced from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Proteome profiling was done using supervised machine learning.
RESULTS
We found an APOE4-specific proteome signature that was independent of cognitive diagnosis and AD pathological biomarkers, and increased risk of progression to cognitive impairment. Proteins were enriched in brain regions including the caudate and cortex and cells including endothelial cells, oligodendrocytes, and astrocytes. Enriched peripheral immune cells included T cells, macrophages, and B cells.
DISCUSSION
APOE4 carriers have a unique CSF proteome signature associated with a strong brain and peripheral immune and inflammatory phenotype that likely underlies APOE4 carriers' vulnerability to cognitive decline and AD.
PubMed: 38915547
DOI: 10.1101/2024.04.18.590160 -
BioRxiv : the Preprint Server For... Jun 2024White matter hyperintensities (WMHs) are commonly detected on T2-weighted magnetic resonance imaging (MRI) scans, occurring in both typical aging and Alzheimer's...
White matter hyperintensities (WMHs) are commonly detected on T2-weighted magnetic resonance imaging (MRI) scans, occurring in both typical aging and Alzheimer's disease. Despite their frequent appearance and their association with cognitive decline, the molecular factors contributing to WMHs remain unclear. In this study, we investigated the transcriptomic profiles of two commonly affected brain regions with coincident AD pathology-frontal subcortical white matter (frontal-WM) and occipital subcortical white matter (occipital-WM)-and compared with age-matched healthy controls. Through RNA-sequencing in frontal- and occipital-WM bulk tissues, we identified an upregulation of genes associated with brain vasculature function in AD white matter. To further elucidate vasculature-specific transcriptomic features, we performed RNA-seq analysis on blood vessels isolated from these white matter regions, which revealed an upregulation of genes related to protein folding pathways. Finally, comparing gene expression profiles between AD individuals with high-versus low-WMH burden showed an increased expression of pathways associated with immune function. Taken together, our study characterizes the diverse molecular profiles of white matter changes in AD compared to normal aging and provides new mechanistic insights processes underlying AD-related WMHs.
PubMed: 38915516
DOI: 10.1101/2024.06.13.598845 -
BioRxiv : the Preprint Server For... Jun 2024Underlying drivers of late-onset Alzheimer's disease (LOAD) pathology remain unknown. However, multiple biologically diverse risk factors share a common pathological...
UNLABELLED
Underlying drivers of late-onset Alzheimer's disease (LOAD) pathology remain unknown. However, multiple biologically diverse risk factors share a common pathological progression. To identify convergent molecular abnormalities that drive LOAD pathogenesis we compared two common midlife risk factors for LOAD, heavy alcohol use and obesity. This revealed that disrupted lipophagy is an underlying cause of LOAD pathogenesis. Both exposures reduced lysosomal flux, with a loss of neuronal lysosomal acid lipase (LAL). This resulted in neuronal lysosomal lipid (NLL) accumulation, which opposed Aβ localization to lysosomes. Neuronal LAL loss both preceded (with aging) and promoted (targeted knockdown) Aβ pathology and cognitive deficits in AD mice. The addition of recombinant LAL and neuronal LAL overexpression prevented amyloid increases and improved cognition. In WT mice, neuronal LAL declined with aging and correlated negatively with entorhinal Aβ. In healthy human brain, LAL also declined with age, suggesting this contributes to the age-related vulnerability for AD. In human LOAD LAL was further reduced, correlated negatively with Aβ , and occurred with polymerase pausing at the LAL gene. Together, this finds that the loss of neuronal LAL promotes NLL accumulation to impede degradation of Aβ in neuronal lysosomes to drive AD amyloid pathology.
SUMMARY
Cellular and molecular drivers of late-onset Alzheimer's disease (LOAD) are unknown, though several risk factors account for the majority of disease incidence . Though diverse in their biological natures, each of these risk exposures converge on a shared pathological progression with the accumulation of amyloid early in the disease. Human genetic and transcriptomic studies suggest a role for altered lipid metabolism , though the mechanism has been unknown. Here, using two common midlife risk exposures for LOAD, we found that dysfunctional lipophagy caused by the loss of lysosomal acid lipase (LAL) promotes early LOAD pathogenesis. Both midlife obesity and heavy alcohol reduced neuronal LAL, causing an increase in neuronal lysosomal lipid, and a subsequent accumulation of Aβ in the extra-lysosomal cytosol. This loss of LAL preceded and promoted Aβ pathology and cognitive deficits in AD mice. The addition of recombinant LAL and neuronal LAL overexpression prevented increases in amyloid and improved cognition. In human brain, LAL declined with age in healthy subjects, similar to rodents, showing robust losses in LOAD subjects with polymerase pausing. Together, this implicates neuronal LAL loss in LOAD pathogenesis and presents LAL as a promising diagnostic, preventative, and/or therapeutic target for AD.
PubMed: 38915509
DOI: 10.1101/2024.06.09.596693 -
Frontiers in Immunology 2024The identification of diagnostic and therapeutic biomarkers for Alzheimer's Disease (AD) remains a crucial area of research. In this study, utilizing the Weighted Gene...
The identification of diagnostic and therapeutic biomarkers for Alzheimer's Disease (AD) remains a crucial area of research. In this study, utilizing the Weighted Gene Co-expression Network Analysis (WGCNA) algorithm, we identified RHBDF2 and TNFRSF10B as feature genes associated with AD pathogenesis. Analyzing data from the GSE33000 dataset, we revealed significant upregulation of RHBDF2 and TNFRSF10B in AD patients, with correlations to age and gender. Interestingly, their expression profile in AD differs notably from that of other neurodegenerative conditions. Functional analysis unveiled their involvement in immune response and various signaling pathways implicated in AD pathogenesis. Furthermore, our study demonstrated the potential of RHBDF2 and TNFRSF10B as diagnostic biomarkers, exhibiting high discrimination power in distinguishing AD from control samples. External validation across multiple datasets confirmed the robustness of the diagnostic model. Moreover, utilizing molecular docking analysis, we identified dinaciclib and tanespimycin as promising small molecule drugs targeting RHBDF2 and TNFRSF10B for potential AD treatment. Our findings highlight the diagnostic and therapeutic potential of RHBDF2 and TNFRSF10B in AD management, shedding light on novel strategies for precision medicine in AD.
Topics: Humans; Alzheimer Disease; Machine Learning; Biomarkers; Molecular Docking Simulation; Gene Regulatory Networks; Gene Expression Profiling; Transcriptome; Female; Male; Receptors, TNF-Related Apoptosis-Inducing Ligand
PubMed: 38915415
DOI: 10.3389/fimmu.2024.1333666 -
Frontiers in Aging Neuroscience 2024The glucagon-like peptide-1 receptor (GLP-1R) agonists reduce glycated hemoglobin in patients with type 2 diabetes. Mounting evidence indicates that the potential of...
The glucagon-like peptide-1 receptor (GLP-1R) agonists reduce glycated hemoglobin in patients with type 2 diabetes. Mounting evidence indicates that the potential of GLP-1R agonists, mimicking a 30 amino acid ligand, GLP-1, extends to the treatment of neurodegenerative conditions, with a particular focus on Alzheimer's disease (AD). However, the mechanism that underlies regulation of GLP-1R availability in the brain with AD remains poorly understood. Here, using whole transcriptome RNA-Seq of the human postmortem caudate nucleus with AD and chronic hydrocephalus (CH) in the elderly, we found that GLP-1R and select mRNAs expressed in glucose dysmetabolism and dyslipidemia were significantly altered. Furthermore, we detected human RNA indicating a deficiency in doublecortin (DCX) levels and the presence of ferroptosis in the caudate nucleus impacted by AD. Using the genome data viewer, we assessed mutability of GLP-1R and 39 other genes by two factors associated with high mutation rates in chromosomes of four species. Surprisingly, we identified that nucleotide sizes of GLP-1R transcript exceptionally differed in all four species of humans, chimpanzees, rats, and mice by up to 6-fold. Taken together, the protein network database analysis suggests that reduced GLP-1R in the aged human brain is associated with glucose dysmetabolism, ferroptosis, and reduced DCX+ neurons, that may contribute to AD.
PubMed: 38915346
DOI: 10.3389/fnagi.2024.1350239 -
Frontiers in Neuroscience 2024Alzheimer's disease (AD) is the most common form of dementia and is characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary Tau tangles in...
Alzheimer's disease (AD) is the most common form of dementia and is characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary Tau tangles in the brain. We previously identified a set of candidate AD microRNAs (miRNAs) in human cerebrospinal fluid (CSF) and used a target prediction pipeline to identify mRNAs and pathways that could potentially be regulated by the miRNAs. Of these pathways, clathrin mediated endocytosis (CME) was selected for further investigation. CME is altered in multiple brain cell types in AD and is implicated in early cellular phenotypes such as enlarged early endosomes and pathogenic processing of Aβ. However, a comprehensive evaluation of major CME hub proteins in humans with AD across multiple brain regions is lacking. Thus, we used immunoblots to evaluate human post-mortem AD and control (CTL) frontal cortex (FC; AD = 22, CTL = 23) and hippocampus (HP; AD = 34, CTL = 22) for changes in Intersectin 1 (ITSN1), Phosphatidylinositol Binding Clathrin Assembly Protein gene (PICALM), Clathrin Light Chain (CLT), FCH and Mu Domain Containing Endocytic Adaptor 1 (FCHO1), Adaptor Related Protein Complex 2 (AP2) Subunit Alpha 1 (AP2A1), and Dynamin 2 (DNM2). Of these, we found that in AD, ITSN1-long (ITSN1-L) was decreased in the FC of males and HP of females, while ITSN1-short was increased in the HP of both males and females. We further evaluated ITSN1-L levels in cortex (CTX) and HP of the 5xFAD mouse model of Aβ pathology at different timepoints during aging and disease progression by immunoblot ( = 5-8 per group). At 3 months, female 5xFAD exhibited an increase of ITSN1-L in CTX but a decrease at 6 and 9 months. Additionally, immunofluorescent staining of 5xFAD primary HP neurons showed an increase of ITSN1-L in matured 5xFAD neurons at 21 and 28 days . Together, our studies show that in AD, isoforms of ITSN1 change in a brain region-and sex-dependent manner. Further, changes in ITSN1-L are transient with levels increasing during early Aβ accumulation and decreasing during later progression. These findings suggest that ITSN1 expression, and consequently CME activity, may change depending on the stage of disease progression.
PubMed: 38915309
DOI: 10.3389/fnins.2024.1426180 -
Acta Neuropathologica Communications Jun 2024Cerebral amyloid angiopathy (CAA) is a highly prevalent and progressive pathology, involving amyloid-β (Aβ) deposition in the cerebral blood vessel walls. CAA is...
Cerebral amyloid angiopathy (CAA) is a highly prevalent and progressive pathology, involving amyloid-β (Aβ) deposition in the cerebral blood vessel walls. CAA is associated with an increased risk for intracerebral hemorrhages (ICH). Insight into the molecular mechanisms associated with CAA pathology is urgently needed, to develop additional diagnostic tools to allow for reliable and early diagnosis of CAA and to obtain novel leads for the development of targeted therapies. Tissue inhibitor of matrix metalloproteinases 4 (TIMP4) is associated with cardiovascular functioning and disease and has been linked to vascular dementia. Using immunohistochemistry, we studied occipital brain tissue samples of 57 patients with CAA (39 without ICH and 18 with ICH) and 42 controls, and semi-quantitatively assessed expression levels of TIMP4. Patients with CAA had increased vascular expression of TIMP4 compared to controls (p < 0.001), and in these patients, TIMP4 expression correlated with CAA severity (τ = 0.38; p = 0.001). Moreover, TIMP4 expression was higher in CAA-ICH compared to CAA-non-ICH cases (p = 0.024). In a prospective cross-sectional study of 38 patients with CAA and 37 age- and sex-matched controls, we measured TIMP4 levels in cerebrospinal fluid (CSF) and serum using ELISA. Mean CSF levels of TIMP4 were decreased in patients with CAA compared to controls (3.36 ± 0.20 vs. 3.96 ± 0.22 ng/ml, p = 0.033), whereas median serum levels were increased in patients with CAA (4.51 ng/ml [IQR 3.75-5.29] vs 3.60 ng/ml [IQR 3.11-4.85], p-9.013). Moreover, mean CSF TIMP4 levels were lower in CAA patients who had experienced a symptomatic hemorrhage compared to CAA patients who did not (2.13 ± 0.24 vs. 3.57 ± 0.24 ng/ml, p = 0.007). CSF TIMP4 levels were associated with CSF levels of Aβ40 (spearman r (r) = 0.321, p = 0.009). In summary, we show that TIMP4 is highly associated with CAA and CAA-related ICH, which is reflected by higher levels in the cerebral vasculature and lower levels in CSF. With these findings we provide novel insights into the pathophysiology of CAA, and more specifically in CAA-associated ICH.
Topics: Humans; Cerebral Amyloid Angiopathy; Male; Female; Tissue Inhibitor of Metalloproteinase-4; Aged; Tissue Inhibitor of Metalloproteinases; Aged, 80 and over; Brain; Middle Aged; Cerebral Hemorrhage; Amyloid beta-Peptides
PubMed: 38915119
DOI: 10.1186/s40478-024-01823-x -
Molecular Neurodegeneration Jun 2024Tau is aberrantly acetylated in various neurodegenerative conditions, including Alzheimer's disease, frontotemporal lobar degeneration (FTLD), and traumatic brain injury...
BACKGROUND
Tau is aberrantly acetylated in various neurodegenerative conditions, including Alzheimer's disease, frontotemporal lobar degeneration (FTLD), and traumatic brain injury (TBI). Previously, we reported that reducing acetylated tau by pharmacologically inhibiting p300-mediated tau acetylation at lysine 174 reduces tau pathology and improves cognitive function in animal models.
METHODS
We investigated the therapeutic efficacy of two different antibodies that specifically target acetylated lysine 174 on tau (ac-tauK174). We treated PS19 mice, which harbor the P301S tauopathy mutation that causes FTLD, with anti-ac-tauK174 and measured effects on tau pathology, neurodegeneration, and neurobehavioral outcomes. Furthermore, PS19 mice received treatment post-TBI to evaluate the ability of the immunotherapy to prevent TBI-induced exacerbation of tauopathy phenotypes. Ac-tauK174 measurements in human plasma following TBI were also collected to establish a link between trauma and acetylated tau levels, and single nuclei RNA-sequencing of post-TBI brain tissues from treated mice provided insights into the molecular mechanisms underlying the observed treatment effects.
RESULTS
Anti-ac-tauK174 treatment mitigates neurobehavioral impairment and reduces tau pathology in PS19 mice. Ac-tauK174 increases significantly in human plasma 24 h after TBI, and anti-ac-tauK174 treatment of PS19 mice blocked TBI-induced neurodegeneration and preserved memory functions. Anti-ac-tauK174 treatment rescues alterations of microglial and oligodendrocyte transcriptomic states following TBI in PS19 mice.
CONCLUSIONS
The ability of anti-ac-tauK174 treatment to rescue neurobehavioral impairment, reduce tau pathology, and rescue glial responses demonstrates that targeting tau acetylation at K174 is a promising neuroprotective therapeutic approach to human tauopathies resulting from TBI or genetic disease.
Topics: Animals; Tauopathies; tau Proteins; Mice; Acetylation; Humans; Immunotherapy; Disease Models, Animal; Mice, Transgenic; Brain Injuries, Traumatic; Brain Injuries; Brain; Neuroprotective Agents
PubMed: 38915105
DOI: 10.1186/s13024-024-00733-9 -
BMC Medicine Jun 2024People with different types of dementia may have distinct symptoms and experiences that affect their quality of life. This study investigated whether quality of life...
BACKGROUND
People with different types of dementia may have distinct symptoms and experiences that affect their quality of life. This study investigated whether quality of life varied across types of dementia and over time.
METHODS
The participants were 1555 people with mild-to-moderate dementia and 1327 carers from the IDEAL longitudinal cohort study, recruited from clinical services. As many as possible were followed for up to 6 years. Diagnoses included were Alzheimer's disease, vascular dementia, mixed Alzheimer's and vascular dementia, Parkinson's disease dementia, dementia with Lewy bodies, and frontotemporal dementia. Self- and informant-rated versions of the Quality of Life in Alzheimer's Disease scale were used. A joint model, incorporating a mixed effects model with random effects and a survival model to account for dropout, was used to examine whether quality of life varied by dementia type at the time of diagnosis and how trajectories changed over time.
RESULTS
The strongest associations between dementia type and quality of life were seen around the time of diagnosis. For both self-ratings and informant ratings, people with Parkinson's disease dementia or dementia with Lewy bodies had lower quality of life scores. Over time there was little change in self-rated scores across all dementia types (- 0.15 points per year). Informant-rated scores declined over time (- 1.63 points per year), with the greatest decline seen in ratings by informants for people with dementia with Lewy bodies (- 2.18 points per year).
CONCLUSIONS
Self-rated quality of life scores were relatively stable over time whilst informant ratings showed a steeper decline. People with Parkinson's disease dementia or dementia with Lewy bodies report particularly low levels of quality of life, indicating the importance of greater attention to the needs of these groups.
Topics: Humans; Quality of Life; Male; Female; Longitudinal Studies; Aged; Dementia; Aged, 80 and over; Middle Aged
PubMed: 38915081
DOI: 10.1186/s12916-024-03492-y -
BMC Geriatrics Jun 2024A prevalent challenge in neuropsychological assessment, particularly when utilizing instruments designed for controlled laboratory environments, is that the outcomes may...
BACKGROUND
A prevalent challenge in neuropsychological assessment, particularly when utilizing instruments designed for controlled laboratory environments, is that the outcomes may not correspond to an individual's real-life status. Accordingly, assessments of visuospatial working memory (VSWM) conducted in such settings might fail to capture certain facets of this function, as it operates in real life. On the other hand, entirely ecological assessments may risk compromising internal validity. This study aimed to develop an intermediate mode of assessment that measures VSWM in older adults by employing a setting, a task, and a response format that aligns closely with both laboratory and ecological assessments. Furthermore, a preliminary investigation was carried out to study the variations in spatial cognition among different demographic groups.
METHODS
In a two-session study, 77 healthy older adults, eight patients with mild cognitive impairment (MCI), and seven patients with Alzheimer's disease (AD) were recruited to complete the wayfinding questionnaire (WQ), the Corsi block-tapping task (CBTT), and the Spatial Memory Table (SMT). The SMT is a novel instrument developed specifically for this study, aiming to provide a more accurate measure of VSWM performance in older adults' everyday life. Test-retest and split-half reliabilities, as well as the face, content, concurrent, convergent, and known-groups validities, were analyzed to investigate the psychometric properties of the SMT.
RESULTS
The analyses were mainly centered on studying the psychometric properties of the SMT. Test-retest reliability (r = .753, p < .001) and split-half reliability (ρSC = 0.747) were found to be acceptable. Concurrent validity using CBTT (r = .264, p = .021), convergent validity using WQ subscales (navigation and orientation: r = .282, p = .014; distance estimation: r = .261, p = .024), and known-groups validity using the SMT scores among people with MCI and AD (χ2 = 35.194, df = 2, p < .001) were also indicative of the instrument's good validity. Data analysis also revealed acceptable levels of face validity (U = 4.50; p = .095) and content validity (CVR ≥ 0.60). As a result of comparing VSWM and wayfinding variables across genders and education levels, a significant difference was observed for navigation and orientation and spatial anxiety between women and men (p < .05). None of the variables were different among education levels.
CONCLUSION
The SMT was found to be a reliable and valid tool for measuring VSWM performance in older adults. Given these findings, the SMT can be regarded as a measure that sufficiently approximates both laboratory and real-life demands for VSWM. Additionally, the instrument demonstrated a preliminary acceptable capacity to differentiate between healthy individuals and those with MCI and AD.
Topics: Humans; Aged; Male; Female; Psychometrics; Memory, Short-Term; Cognitive Dysfunction; Neuropsychological Tests; Aged, 80 and over; Alzheimer Disease; Space Perception; Spatial Memory; Middle Aged
PubMed: 38914947
DOI: 10.1186/s12877-024-05140-9