Research Project
10197457
PROJECT SUMMARY Aging is the greatest risk factor to ?-synucleinopathy, a group of neurodegenerative diseases with severe cognitive impairmentand progressive motor dysfunction and dementia, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) and half of Alzheimer's disease patients (AD). Dementia is a common symptom in ?-synucleinopathies: DLB is the 2nd most common dementia after Alzheimer's disease (AD) accounting for 30% of dementia cases; Around 30% of AD cases also suffer from ?-synucleinopathy resulting in a more rapid and severe cognition decline than AD alone. PD is the 2nd most common neurodegenerative disease, and greater than 50% of PD cases develop PDD. In addition to cognitive and memory dysfunctions, patients with dementia also suffer from anxiety, depression and mood swings. Although ?-syn pathology is highly associated with dementia, the underlying aging-related mechanism driving the pathogenesis and contributing to their progression is not known and there is no available disease modifying therapy yet. Based on substantial postmortem analysis, Braak et al. demonstrated that ?-syn pathology spreads in a stereotyped fashion from the vagus to the brain, which may initiate in the gastrointestinal tract. Particularly, nearly all the DLB and PDD cases present with ?-syn pathology in the gut. Both clinical and experimental observations support that pathogenic ?-syn spreading is a master trigger that drives ?-synucleinopathy. In our gut-brain ?-synucleinopathy (GBAS) mouse model, gut-injection of pathogenic ?-synuclein (?-syn) can recapitulate ?-syn pathology gut-brain spreading and cognitive impairment. In our preliminary studies, heterochronic blood exchange (HBE) from young mice inhibited pathogenic ?-syn transmission and neuroinflammation in aged mice, suggesting an HBE-transferred phenotype that may effectively inhibit ?-synucleinopathy. We identified lymphocyte-activation gene 3 (LAG3)1, a major receptor of pathologic ?-syn transmission. To identify the mechanism underlying rejuvenation and accelerated aging event, we further identified two novel LAG3-related and aging-regulating proteins that can mediate pathogenic ?-syn transmission. Our studies support the feasibility to modulate plasma levels of FGL1 and sLAG3 in aged mice by the HBE approach. To determine the underlying mechanism if FGL1 and sLAG3 in the plasma are molecular mediators essential for the inhibitory effects of HBE on ?-synucleinopathy an d related cognitive impairment, we have established a rigorous and robust experimental system combining the HBE approach, the GBAS model, genetically engineered mice without these factors, and recombinant FGL1 and sLAG3 proteins, for comprehensive gain- and loss-of-function analysis. Our Central Hypothesis is to identify the underlying mechanism that HBE inhibits ?-synucleinopathy and related cognitive impairment through FGL1 and sLAG3. FGL1 functions as a rejuvenation factor to inhibit pathologic ?-syn spreading in the gut-brain axis and alleviate consequent neurodegeneration, neuroinflammation, and cognitive impairment. sLAG3 acts as an age-acceleration factor contributing to the pathogenesis and with antagonistic function to FGL1. Strikingly, human postmortem evidence shows that ?-syn pathology is observed first in the gastrointestinal system and then spreads to the brain in a stereotyped fashion. Recently, our collaborator Dr. Dawson developed a novel Gut-Brain ?-synucleinopathy (GBAS) model, a sporadic ?-synucleinopathy model recapitulating pathologic ?-syn spreading among multiple organs and brain regions in patients. However, it remains largely unknown how aging-associated blood-borne components modulate ?-synucleinopathy. As the foundation of this project, we identified lymphocyte-activation gene 3 (LAG3), a major receptor of pathologic ?-syn transmission. Our preliminary results showed that heterochronic blood exchange (HBE) from young mice can inhibit pathologic ?-syn transmission to cells and inflammation in aged mice. We further identified two blood-borne aging-modulated proteins that regulate LAG3-mediated pathologic ?-syn transmission. The first plasma protein fibrinogen-like protein (FGL1) as the major inhibitory ligand of LAG3, is decreased by aging and inhibits ?-syn transmission. The second plasma protein sLAG3 is the soluble form of LAG3 protein, and it is increased by aging and promotes ?-syn transmission. Our studies also support the feasibility to use HBE approach to modulate plasma levels of FGL1 and sLAG3 in aged mice by young blood. Our Central Hypothesis is that HBE with young blood inhibits ?-synucleinopathy through two aging-associated circulatory proteins (FGL1 and sLAG3) essential for LAG3-mediated pathologic ?-syn transmission. FGL1 functions as a rejuvenation factor to inhibit pathologic ?-syn spreading in the gut-brain axis and consequent neurodegeneration, neuroinflammation, and behavioral deficits associated ?-synucleinopathy. sLAG3 acts as an age-acceleration factor with antagonistic functions to FGL1. In specific aim 1, we propose to determine if HBE ameliorates ?-synucleinopathy and related cognitive impairment by increasing aging-reduced FGL1 to inhibit pathological ?-syn spreading. In specific aim 2, we propose to determine if HBE ameliorates ?-synucleinopathy and related cognitive impairment by decreasing aging-induced sLAG3 to inhibit pathological ?-syn spreading. Modulating plasma factors is a novel strategy to inhibit pathologic ?-syn spreading and treating ?-synucleinopathy and dementia. Positive results from this study will justify the development of novel ?-synucleinopathy therapies based on plasma factor modulation. Novel molecular insights from this project will lay a solid foundation for the optimization and clinical translation of ?-synucleinopathy therapies based on FGL1 and sLAG3 modulation.
