Year: 2024
Type: dissertation
Abstract: To date, neurodegenerative diseases remain with lackluster treatment options. Diseases such as Alzheimer’s are defined based on proteinopathic inclusions, and these inclusions have been the targets of most therapeutic development. The premise that simply addressing these inclusions will be sufficient for therapeutics is poorly supported. Here, I attempt to build an evidence base using selective vulnerability as a substrate to work towards more biologically informed disease-modifying therapeutics. First, I examine the physiological underpinnings of a potent risk factor for dementia and other age-related diseases – social isolation. In humans, social isolation has well-established epidemiological associations with dementia, cardiovascular disease, immune system dysfunction, metabolic disorders, and mental health disorders. Mice exposed to long-term social isolation are studied across several organ systems. Associations with the stressor are detected in renal structure and blood-brain-barrier dysfunction; however, I find that mice are a poor model of social isolation.Next, I examine a potential mechanism underlying why neurons with tau proteinopathic inclusions die. The best correlate of functional decline in neurodegeneration is neuron loss, so focusing on processes of neuron loss might confer better therapeutics. Here, I find that the Ras GTPase, Rhes, is dysregulated in neurons harboring tau proteinopathic inclusions in sporadic tauopathies. This study reinforces in vitro and in vivo work done in models of familial tauopathy demonstrating that a farnesyltransferase inhibitor may suppress neurodegeneration in tauopathies. I then approach selective vulnerability by focusing on the neuromodulatory subcortical system. Parts of the neuromodulatory subcortical system are affected early in Alzheimer’s disease and feature a wide gradient of selective vulnerability and resilience. Here, I find pathways related to cholesterol homeostasis and stress hormone signaling to the noradrenergic locus coeruleus that differentiate it from the more resilient substantia nigra. I close by focusing on the epistemological frameworks used to study neurodegenerative disease and comment on how a focus on selective vulnerability may drive significant paradigm changes in the field. Overall, this dissertation provides evidence of pathophysiology that may drive neurodegenerative diseases and adverse outcomes of stress disorders.
Author: Ehrenberg, Alexander James
Institution: University of California, Berkeley
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funders: National Science Foundation, Alzheimer's Association, Biogen, Alzheimer's Disease Neuroimaging Initiative, BioClinica, EU Joint Programme – Neurodegenerative Disease Research, Global Brain Health Institute, Alzheimer's Society, National Institute for Health and Care Research, University College London, Deutsche Forschungsgemeinschaft, University of Sydney, Bundesministerium für Bildung und Forschung, Hjärnfonden, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, Göteborgs Universitet, Alzheimerfonden, Servier, UK Dementia Research Institute, National Institutes of Health, Genentech, University of California, San Francisco, Medical Research Council, National Health and Medical Research Council, Wallenberg Centre for Molecular and Translational Medicine, National Institute on Aging, National Institute of Neurological Disorders and Stroke
Awards: G140313323, Central noradrenergic mechanisms of cerebrovascular pathology in Alzheimer's disease, G1442296065, Linking tau proteostasis with neuronal activity in FTD, G282710236, G2915930666, G3097568876, Impact of locus coeruleus-derived tau pathology in a rodent model of early Alzheimer's disease, G33726220, G3810827041, Deciphering the dynamic neural basis of cognition and dementia, Novel Biomarkers Related to Sleep-Wake Alterations in Alzheimer’s disease, Characterizing sleep-wake activity patterns to detect early Alzheimer's disease in normal older individuals, AMP-AD Brain Proteomic Network Enhancement, Validation, and Translation into CSF Biomarkers, Local and global consequences of hyperphosphorylated tau in the locus coeruleus in Alzheimer's Disease, NiPARK - Neuromelanin in Parkinson - Neuromelanin Imaging in Substantia Nigra und Locus Coeruleus, Does the central noradrenergic system play a role in agitation in Alzheimer's disease?, G7473646402, G7553336952, G787013686, GRK 2413: Die alternde Synapse molekulare, zelluläre und verhaltensbiologische Mechanismen des kognitiven Leistungsabfalls, G8339569982, G8342502279, G8650669854, What determines amyloid beta aggregation and toxicity in Alzheimer’s disease?, Emotion-cognition interactions and aging, SFB 1436: Neuronale Ressourcen der Kognition, TREAT AD, Michigan Alzheimer's Disease Research Center, Neuropathological changes underlying clinical heterogeneity in Alzheimer dise, Stanford Alzheimer's Disease Research Center, Goizueta Alzheimer's Disease Research Center, New Approaches to Dementia Heterogeneity
OpenAlex ID: W7048727250