Erik Roberson - US grants

[unreadable] DESCRIPTION (provided by applicant): Alzheimer's disease (AD) and related neurodegenerative disorders are a major source of morbidity and mortality, particularly with the increasingly aged population of the United States. Pathology involving the microtubule-associated protein tau is a common feature of many such diseases, including AD, frontotemporal lobar degeneration, many forms of Parkinsonism, and amyotrophic lateral sclerosis. This proposal describes a training plan for the development of an academic neurologist interested in the molecular mechanisms of dementing diseases, particularly tau. The research plan focuses on the role of tau in AD pathology testing the hypothesis that tau is critical for the neuronal dysfunction induced by amyloid-beta (Abeta) in amyloid precursor protein (APP) transgenic mice. Preliminary studies indicate that tau removal prevents most behavioral and pathological abnormalities in APP mice at 4-7 months of age. Specific Aim 1 extends this observation, studying older APP mice to examine how long the effects of Abeta remain tau-dependent and determining the effect of changing tau expression after AD is produced and dysfunction is apparent. Specific Aim 2 considers signaling pathways that might mediate interactions between Abeta and tau, with an emphasis on the tyrosine kinase Fyn. Specific Aim 3 studies downstream mechanisms for tau's role, specifically regulation of axonal transport and APP processing. The candidate has a Ph.D. in neuroscience and an M.D. with residency training in neurology. He is committed to a career in academic medicine studying the basic mechanisms of neurodegenerative diseases. To that end, the research proposal and career development plan build on his prior training in basic neuroscience, biochemistry, electrophysiology, and clinical neurology to provide expertise in transgenic mouse models, behavioral analysis, histology, and viral vectors. Dr. Lennart Mucke, who specializes in transgenic mouse models of neurodegenerative disease, is the candidate's sponsor. The mentoring and research experience described in this proposal will facilitate the candidate's goal of an independent faculty research position. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The incidence of Alzheimer's disease (AD) is steadily increasing with the aging of the U.S. population, and there are still no highly effective treatments. Amyloid-¿ peptides (A¿) and the microtubule-associated protein tau compose the pathological hallmarks of AD. Considerable effort has been devoted to development of anti- A¿ therapeutics, but disappointing results of early clinical trials has also broadened interest in other targets, notably tau. However, targeting a protein like tau that is abundant in the normal brain requires adequate knowledge of how it contributes to disease, and our understanding of tau's role in AD pathogenesis remains incomplete, hampering development of tau-based therapies for AD. We recently found that reducing tau expression has robust protective effects in multiple mouse models of AD, preventing cognitive deficits, premature mortality, impairment of synaptic plasticity, and epileptiform activity. These observations form the basis of the current application, capitalizing on this unique opportunity to understand how tau mediates or enables the effects of A¿. This application uses a new conditional mouse model of tau reduction to address several questions related to tau's role downstream of A¿ in AD-related pathogenesis. In Aim 1, we address the potential therapeutic relevance of tau reduction by determining if tau reduction in adulthood is protective in mouse models of AD. In Aim 2, we address the cellular mechanisms underlying these effects by determining the effects of tau reduction in excitatory vs. inhibitory neurons. In Aim 3, we test a hypothesized molecular mechanism for these protective effects by determining how tau reduction prevents altered expression of ion channels controlling cellular excitability.

PROJECT SUMMARY/ABSTRACT The recent identification of novel genetic risk factors for Alzheimer's disease (AD) may help define new pathogenic mechanisms and therapeutic targets. BIN1 is the second-leading genetic risk factor for AD, after only APOE, and strong genetic, epigenetic, and neuropathological evidence now supports its association with AD. However, it remains unclear how BIN1 contributes to AD. Accumulating evidence points to reduction of the neuronal isoforms of BIN1 in AD, but the effect of losing these BIN1 isoforms on neuronal function and AD pathogenesis is a major knowledge gap. We have developed several tools to address the role of BIN1 in the brain, including BIN1 conditional knockout mice to reduce BIN1 selectively throughout the brain or in excitatory or inhibitory neurons, methods of expressing different BIN1 constructs in neurons either in culture or in vivo in specific neuronal populations, and primary neuron assays of the effects of BIN1 on neuronal activity. Our preliminary studies using these tools, described in this application, provide evidence for bidirectional regulation of neuronal activity by BIN1 and an important role in interneurons, which is particularly interesting in light of multiple data streams supporting a role for neuronal hyperexcitability in early stages of AD. The overarching hypothesis we will address in this proposal is that loss of neuronal BIN1 isoforms reduces neuronal activity, particularly in parvalbumin interneurons, leading to increased network hyperexcitability and impairment of gamma oscillations. This project will examine several aspects of this hypothesis. We will determine the effects of BIN1 loss in excitatory vs. inhibitory neurons on neuronal activity and susceptibility to network hyperexcitability, measuring the effects on BIN1 loss at the cellular level by patch-clamp electrophysiology and at the network level using EEG. We will determine mechanisms by which BIN1 regulates neuronal activity through structure-function analysis and manipulating BIN1 specifically in parvalbumin interneurons, measuring gamma oscillations and cognitive function. We will determine if lower BIN1 levels exacerbate pathogenesis in mouse models of AD, assaying the effects of both increasing and decreasing BIN1 in interneurons in mouse models of AD to directly test the hypothesis that loss of interneuron BIN1 contributes to A?-induced dysfunction. These studies will illuminate mechanism by which a leading genetic risk factor contributes to AD, identify specific neuronal populations involved, and determine the effects of these changes on brain networks contributing to cognition.

PROJECT SUMMARY Converging evidence indicates that neuronal and network hyperexcitability is an important early event in Alzheimer disease (AD) patients. The cellular and molecular basis of this hyperexcitability is a critical area of investigation and the presence of similar hyperexcitability in animal models enables studies to dissect underlying mechanisms. A key insight is that hyperexcitability in both AD patients and mouse models has a strong diurnal rhythm. Emerging data from both humans and animal models indicate that neural excitability in the forebrain is under circadian control, altering seizure thresholds and epileptiform activity. Circadian variation in cellular function is driven by transcriptional molecular clocks expressed in most cells, and molecular clock ablation increases AD pathology. We have compelling preliminary evidence for rhythmic variation in neuronal excitability that is at least partly due to circadian regulation of the membrane properties of inhibitory interneurons, especially fast-spiking cells that express parvalbumin ? a cell type implicated in AD. Given that molecular and physiological rhythms in hippocampus are disrupted in AD patients and AD mouse models, we propose rigorous experiments to test the hypothesis that dysregulation of the molecular clock and resulting changes in PV+ interneuron gene expression and activity contributes to AD-related neuronal hyperexcitability. Specifically, we will evaluate the differences in circadian clock and clock-controlled gene expression in PV+ interneurons in a mouse model of AD, using a combination of RNA sequencing, state-of-the-art bioinformatics, and recently developed tools to evaluate molecular clock rhythmicity and transcription in a cell-specific manner (Aim 1). We will use patch-clamp electrophysiology to determine if AD-related impairment of the circadian clock alters day-night differences in neurophysiological properties of PV+ interneurons, causing hyperexcitability (Aim 2). Finally, we will utilize an innovative chemogenetic chronotherapeutic approach to manipulate PV+ interneuron physiology to determine whether reinstating the normal circadian regulation of PV+ interneuron electrophysiological properties protects against AD-related hyperexcitability, cognitive impairment, and pathology (Aim 3). The proposed studies led by a strong interdisciplinary team uses powerful approaches to determine how disruption of circadian rhythms facilitates neuronal hyperexcitability that contributes to early stages of AD. Understanding these mechanisms may catalyze development of behavioral or pharmacologic interventions.

PROJECT SUMMARY/ABSTRACT The Administrative Core will provide the organizational base for all UAB ADRC activities. To support accomplishing the ADRC?s scientific goals and the continued development of the center during the exploratory phase, we propose the following Administrative Core aims: to provide sound leadership, strategic planning, and organizational structure for ADRC operations; to establish and coordinate meetings of Internal and External Advisory Committees to provide evaluation, guidance, and support to ADRC leadership; to ensure efficient, accurate, and secure management of ADRC data; to facilitate transition to local leadership of the Neuropathology Core; to manage resource allocation and secure institutional support for ADRC activities; to foster and enable AD research at UAB by sponsoring seminars, symposia, and interdisciplinary conferences focusing on the latest developments in the field; to promote ADRC scientific interactions and sharing of Center resources with national Alzheimer?s disease research initiatives, including NACC, NCRAD, and NIAGADS; to communicate the ADRC?s progress and activities to our community; and to assure compliance with NIH policies.

PROJECT SUMMARY/ABSTRACT The thematic focus of the proposed exploratory UAB Alzheimer?s Disease Research Center (ADRC) is on Deep South disparities in Alzheimer?s disease. Individuals born in the Deep South (traditionally defined as the five-state region spanning LA, MS, AL, GA, and SC) have high rates of Alzheimer?s disease (AD) and related dementias relative to other regions. The most likely explanation for this observation is that several large populations disparately impacted by AD are concentrated in the Deep South. For example, the region is home to the nation?s largest population identifying as Black or African American, who are estimated to be at as much as double the risk of AD. The Deep South also a very large rural population, with disparities in social determinants of health (income, education, health care access, and related factors) that strongly influence AD risk. Likewise, vascular risks and related medical comorbidities such as diabetes, cerebrovascular disease, and obesity are each most prevalent in the Deep South and associated with AD. Our vision is a future in which these Deep South disparities in AD are eliminated. Realizing this vision requires a deeper understanding of the unique factors driving AD in the region, which is the goal of our center. We have already launched our cores in a pilot phase with institutional support and propose during the P20 phase to consolidate this collaborative team and demonstrate our capacity for outreach, recruitment, enrollment, and data/biospecimen collection from a representative Deep South population, in preparation for a future P30-funded Center. We will build on our initial success in establishing a cohort with substantial inclusion of Black or African American participants, create a second recruitment and evaluation site in western Jefferson County to facilitate minority and rural participation, and generate evidence of our capacity to collect a unique and comprehensive collection of data and biospecimens informative about Deep South disparities in AD.