2019 Awardees
Ian Mahar, PhD
Project Title: Brodmann Area 25 in the etiology of depression in Alzheimer’s disease and CTE
Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE) share some common neuropathological and symptomatic features, with elevated prevalence of depression and depressive symptoms found in both disorders. Depression outside of neurodegenerative contexts has been widely studied, with several possible etiological mechanisms supported. However, the neurobiological etiology of depression in the context of AD and CTE has been largely or wholly unexamined, despite the widespread prevalence and substantial distress elicited. It is unknown whether mechanisms underlying depression in neurodegenerative cases are similar to those found for depression not induced by degenerative neuropathology, or conversely whether unknown mechanisms associated with neurodegeneration are responsible for depression in AD or CTE. Using postmortem samples, Ian and his team will examine the association of neurodegenerative pathology in AD and CTE with depression, by comparing neurodegenerative cases with depression to those without. This will focus on Brodmann area 25 (BA25), which is heavily implicated in depression and antidepressant effects. AIM 1: Compare verified AD/CTE cases who had depression to cases that did not have depression in terms of ptau or Aβ pathology in BA25. AIM 2: Examine whether localized neuroinflammation or gliosis (previously associated locally with AD/CTE pathology) is altered in BA25, as this may be etiologically related to the development of depressive phenotypes. AIM 3: Determine whether any alterations (identified in AIMS 1 and 2) distinguishing depressed from non-depressed neurodegenerative cases and controls are reduced in individuals that received particular antidepressant treatments.
Zhi Ruan, PhD
Project Title: P2X7R inhibitor blocks exosome secretion and reduces proteopathic Tau accumulation in P301S tauopathy mouse model.
The best-correlated pathology to clinical onset of Alzheimer’s disease (AD) is neurofibrillary tangles, or intracellular aggregates of hyperphosphorylated tau protein (pTau) in hippocampal regions. Great progress in drug development based on Tau pathology has been made during past decades, however, no such drug works in clinical until now. Recently, emerging studies suggest that exosomes may be the mediator of tau propagation in AD brain and targeting on the block of exosome secretion from microglia, leading to halt the Tau propagation in the brain or even cue AD finally. The P2X7 receptor (P2X7R) is an ATP-gated cation channel, highly expressed in microglia, involved in AD pathobiology. Series of studies suggested that pharmacological inhibition or genetic deletion of P2X7R could alter exosome secretion triggered by ATP stimulation. Zhi and his team will be the first time to determine if there is any relationship between the level of Tsg101 in the brain and the severity of the AD, as well as the relationship with Tau aggregates. The objective of this study is to discover novel Tau-based treatment for AD and explore the potential molecular mechanisms of the candidates, and to validate the findings in human brain using BU ADC Brain Bank.
Alice Cronin-Golomb, PhD
Project Topic: Sleep, memory consolidation and markers of brain pathology in presymptomatic Alzheimer’s disease
Alzheimer’s Disease (AD)-related neurodegeneration can induce abnormalities of sleep pattern and quality, which in turn may lead to memory impairment. It has been suggested that sleep disturbance causes an increase in amyloid beta and tau, two brain proteins associated with AD. Further, the relationship between sleep and amyloid deposition is thought to be bidirectional—namely, sleep disruption leads to amyloid deposition, and amyloid deposition may lead to additional sleep disturbance.
Memory consolidation, the process by which initial memories become long term representations, has been linked to the integrity of slow-wave sleep (SWS). It has been suggested that sharp-wave ripples during SWS play a crucial role in strengthening and replaying newly learned information in the hippocampus, which is critical for the long-term storage of memory within the neocortex. These memory reactivations are also thought to enhance plasticity within medial temporal lobe structures. How SWS is
impacted by incipient AD-related brain pathology, and how SWS disruption may lead to downstream memory consolidation problems in preclinical stages of AD is not fully understood. To address this gap in knowledge, Alice and her team will work with an extraordinary kindred population of approximately 5,000 individuals from Antioquia, Colombia, which contains roughly 1,800 carriers of a Presenilin1 (PSEN1) E280A mutation, causing autosomal dominant Alzheimer’s disease (ADAD). These carriers have a homogenous disease course, and are genetically destined to develop mild cognitive impairment in their mid-forties. For this proposal, Alice and her team will use PET imaging and polysomnographic (PSG) measures to examine whether abnormalities in objective sleep physiology, as measured by PSG sleep patterns, are present in pre symptomatic ADAD, and are associated with accumulation of AD pathological proteins (amyloid-beta and tau), several years before estimated clinical onset. Alice will also aim to examine whether abnormalities in objective sleep physiology may predict changes in long-term memory consolidation in preclinical AD. This study will greatly improve our understanding of the relationships between AD neuropathological changes and the onset of sleep disturbance and cognitive decline in preclinical stages of AD, decades before symptoms begin. Findings from this study will also help inform the design and analysis of prevention interventions.