Biology subjects

Quicksall, Z.

Publications and source records attributed to Quicksall, Z..

4 recordsLinked to original sources

bioRxiv2025

Integrative Epigenomic Landscape of Alzheimer's Disease Brains Reveals Oligodendrocyte Molecular Perturbations Associated with Tau

Alzheimers disease (AD) brains are characterized by neuropathologic and biochemical changes that are highly variable across individuals. Capturing epigenetic factors that associate with this variability can reveal novel biological insights into AD pathophysiology. We conducted an epigenome-wide association study of DNA methylation (DNAm) in 472 AD brains with neuropathologic measures (Braak stage, Thal phase, and cerebral amyloid angiopathy score) and brain biochemical levels of five proteins (APOE, amyloid-{beta} (A{beta})40, A{beta}42, tau, and p-tau) core to AD pathogenesis. Using a novel regional methylation (rCpGm) approach, we identified 5,478 significant associations, 99.7% of which were with brain tau biochemical measures. Of the tau-associated rCpGms, 93 had concordant associations in external datasets comprising 1,337 brain samples. Integrative transcriptome-methylome analyses uncovered 535 significant gene expression associations for these 93 rCpGms. Genes with concurrent transcriptome-methylome perturbations were enriched in oligodendrocyte marker genes, including known AD risk genes such as BIN1, myelination genes MYRF, MBP and MAG previously implicated in AD, as well as novel genes like LDB3. We further annotated the top oligodendrocyte genes in an additional 6 brain single cell and 2 bulk transcriptome datasets from AD and two other tauopathies, Picks disease and progressive supranuclear palsy (PSP). Our findings support consistent rCpGm and gene expression associations with these tauopathies and tau-related phenotypes in both bulk brain tissue and oligodendrocyte clusters. In summary, we uncover the integrative epigenomic landscape of AD and demonstrate tau-related oligodendrocyte gene perturbations as a common potential pathomechanism across different tauopathies.

genomics↗

bioRxiv2024

Large- Scale Deep Proteomic Analysis in Alzheimer's Disease Brain Regions Across Race and Ethnicity

AbstractO_ST_ABSIntroductionC_ST_ABSAlzheimers disease (AD) is the most prevalent neurodegenerative disease, yet our comprehension predominantly relies on studies within the non-Hispanic White (NHW) population. Here we aimed to provide comprehensive insights into the proteomic landscape of AD across diverse racial and ethnic groups. MethodsDorsolateral prefrontal cortex (DLPFC) and superior temporal gyrus (STG) brain tissues were donated from multiple centers (Mayo Clinic, Emory University, Rush University, Mt. Sinai School of Medicine) and were harmonized through neuropathological evaluation, specifically adhering to the Braak staging and CERAD criteria. Among 1105 DLPFC tissue samples (998 unique individuals), 333 were from African American donors, 223 from Latino Americans, 529 from NHW donors, and the rest were from a mixed or unknown racial background. Among 280 STG tissue samples (244 unique individuals), 86 were African American, 76 Latino American, 116 NHW and the rest were mixed or unknown ethnicity. All tissues were uniformly homogenized and analyzed by tandem mass tag mass spectrometry (TMT-MS). ResultsAs a Quality control (QC) measure, proteins with more than 50% missing values were removed and iterative principal component analysis was conducted to remove outliers within brain regions. After QC, 9,180 and 9,734 proteins remained in the DLPC and STG proteome, respectively, of which approximately 9,000 proteins were shared between regions. Protein levels of microtubule-associated protein tau (MAPT) and amyloid-precursor protein (APP) demonstrated AD-related elevations in DLPFC tissues with a strong association with CERAD and Braak across racial groups. APOE4 protein levels in brain were highly concordant with APOE genotype of the individuals. DiscussionThis comprehensive region resolved large-scale proteomic dataset provides a resource for the understanding of ethnoracial-specific protein differences in AD brain.

neuroscience↗

bioRxiv2022

Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer's Disease related proteins

Alzheimers disease (AD) is neuropathologically characterized by amyloid-beta (A{beta}) plaques and neurofibrillary tangles. Main protein components of these hallmarks include A{beta}40, A{beta}42, tau, phospho-tau and APOE. With the exception of the APOE-{varepsilon}4 variant, genetic risk factors associated with brain biochemical measures of these proteins have yet to be characterized. We performed a genome-wide association study in brains of 441 AD patients for quantitative levels of these proteins collected from three distinct fractions reflecting soluble, membrane-bound and insoluble biochemical states. We identified 123 genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD- related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways. Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest that each have unique genetic architecture and biological pathways that influence their specific biochemical states in the brain. Our novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins.

genetics↗

bioRxiv2021

Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways

The S209F variant of Abelson Interactor Protein 3 (ABI3) increases risk for Alzheimers disease (AD), but little is known about ABI3 function. RNAscope showed Abi3 is expressed in microglial and non-microglial cells, though its increased expression appears to be driven in plaque-associated microglia. Here, we evaluated Abi3-/- mice and document that both Abi3 and its overlapping gene, Gngt2, are disrupted in these mice. Expression of Abi3 and Gngt2 are tightly correlated, and elevated, in rodent models of AD. RNA-seq of the Abi3-Gngt2-/- mice revealed robust induction of an AD-associated neurodegenerative signature, including upregulation of Trem2, Plcg2 and Tyrobp. In APP mice, loss of Abi3-Gngt2 resulted in a gene dose- and age-dependent reduction in A{beta} deposition. Additionally, in Abi3-Gngt2-/- mice, expression of a pro-aggregant form of human tau exacerbated tauopathy and astrocytosis. Further, the AD-associated S209F mutation alters the extent of ABI3 phosphorylation. These data provide an important experimental framework for understanding the role of Abi3-Gngt2 function in AD. Our studies also demonstrate that manipulation of glial function could have opposing effects on amyloid and tau pathology, highlighting the unpredictability of targeting such pathways in AD.

neuroscience↗