Biology subjects

Higginbotham, L. A.

Publications and source records attributed to Higginbotham, L. A..

3 recordsLinked to original sources

bioRxiv2023

Transcriptomic network analysis of brain and bone reveals shared molecular mechanisms underlyingAlzheimer's Disease and related dementias and Osteoporosis

Alzheimers disease and related dementias (ADRD) and Osteoporosis (OP) are two prevalent diseases of aging with numerous epidemiological associations, but the underlying molecular mechanisms contributing to this association are unknown. We used WGCNA (weighted gene co-expression network analysis) to develop transcriptomic networks in bone and brain tissue using two different studies to discover common molecular mechanisms. We used RNA-sequencing data from the dorsolateral prefrontal cortex tissue of autopsied brains in 629 participants from ROSMAP (Religious Orders Study and the Memory and Aging Project), including a subset of 298 meeting criteria for inclusion in five ADRD categories and the full set in a secondary analysis, and RNA array data from transiliac bone in 84 participants from the Oslo study of postmenopausal women. After developing each network, we analyzed associations between modules (groups of co-expressed genes) with multiple bone and neurological traits, examined overlap in modules between networks, and performed pathway enrichment analysis to discover conserved mechanisms. We discovered three modules in ROSMAP that showed significant associations with ADRD and bone related traits and four modules in Oslo that showed significant associations with multiple bone outcomes. We found significant module overlap between the two networks, most notably among those modules linked to canonical Wnt signaling and skeletal tissue homeostasis and development. These results were preserved with a network from the full ROSMAP cohort (n=629), which included a broader spectrum of participants. Our results require validation in experimental studies but show support for Wnt signaling as an important driver of pathology in OP and ADRD. We additionally show a strong link between Dementia with Lewy bodies and bone outcomes. These results have translational significance in the development of novel treatments and biomarkers for both ADRD and OP.

neuroscience↗

bioRxiv2022

Unbiased Classification of the Human Brain Proteome Resolves Distinct Clinical and Pathophysiological Subtypes of Cognitive Impairment

The hallmark amyloid-{beta} and tau deposition of Alzheimers disease (AD) represents only a fraction of its diverse pathophysiology. Molecular subtyping using large-scale -omic strategies can help resolve this biological heterogeneity. Using quantitative mass spectrometry, we measured ~8,000 proteins across >600 dorsolateral prefrontal cortex tissues from Religious Orders Study and Rush Memory and Aging Project participants with clinical diagnoses of no cognitive impairment, mild cognitive impairment (MCI), and AD dementia. Unbiased classification of MCI and AD cases based on individual proteomic profiles resolved three classes with expression differences across numerous cell types and biological ontologies. Two classes displayed molecular signatures atypical of those previously observed in AD neurodegeneration, such as elevated synaptic and decreased inflammatory markers. In one class, these atypical proteomic features were associated with clinical and pathological hallmarks of cognitive resilience. These results promise to better define disease heterogeneity within AD and meaningfully impact its diagnostic and therapeutic precision.

neuroscience↗

bioRxiv2019

A Consensus Proteomic Analysis of Alzheimer’s Disease Brain and Cerebrospinal Fluid Reveals Early Changes in Energy Metabolism Associated with Microglia and Astrocyte Activation

Our understanding of the biological changes in the brain associated with Alzheimers disease (AD) pathology and cognitive impairment remains incomplete. To increase our understanding of these changes, we analyzed dorsolateral prefrontal cortex of control, asymptomatic AD, and AD brains from four different centers by label-free quantitative mass spectrometry and weighted protein co-expression analysis to obtain a consensus protein co-expression network of AD brain. This network consisted of 13 protein co-expression modules. Six of these modules correlated with amyloid-{beta} plaque burden, tau neurofibrillary tangle burden, cognitive function, and clinical functional status, and were altered in asymptomatic AD, AD, or in both disease states. These six modules reflected synaptic, mitochondrial, sugar metabolism, extracellular matrix, cytoskeletal, and RNA binding/splicing biological functions. The identified protein network modules were preserved in a community-based cohort analyzed by a different quantitative mass spectrometry approach. They were also preserved in temporal lobe and precuneus brain regions. Some of the modules were influenced by aging, and showed changes in other neurodegenerative diseases such as frontotemporal dementia and corticobasal degeneration. The module most strongly associated with AD pathology and cognitive impairment was the sugar metabolism module. This module was enriched in AD genetic risk factors, and was also highly enriched in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from the sugar metabolism module were increased in cerebrospinal fluid from asymptomatic AD and AD cases, highlighting their potential as biomarkers of the altered brain network. In this study of >2000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brain that may serve as therapeutic targets and fluid biomarkers for the disease.

systems biology↗