Role of SUMO Conjugation in Alzheimer s Disease-Related Impairment of Synaptic Function and Memory Induced by Abnormal Tau Following TBI
Abstract
The long-term goal of this work is to alleviate the burdens that traumatic brain injury (TBI) and Alzheimer’s disease (AD) impose on affected individuals and caregivers by providing the knowledge necessary to develop effective preventative or therapeutic strategies for these conditions. TBI is arguably the most well-established, non-genetic risk factor for dementia, including AD. Military personnel and civilians that experience a TBI are at an increased risk of developing AD and related neurological disorders that can lead to long-term cognitive and behavioral impairments, including dementia, aggression, memory loss, and depression. The Department of Veterans Affairs (VA)/Department of Defense (DOD) defines TBI as mechanically induced structural compromise and or disruption of normal brain function. The mechanical stimulus may be a blunt impact (such as a blow to the head), acceleration/deceleration of the head leading to an inertia-driven deformation of the brain tissue, a penetrating injury (such as a gun-shot wound), or blast exposure, which may encompass all of these mechanisms in addition to injury due to shock wave loading. Over 5 million Americans currently are affected by AD, which is estimated to grow to 13 million by 2050 with a cost of care to treat patients of about $203 billion annually. The prevalence of AD in the Veteran population is the same as in the civilian population; however, the number of affected individuals is expected to increase dramatically, not only as the Veteran population ages, but also because of the increased incidence of TBI. On the histological level, both AD and TBI-associated neurodegeneration are characterized by aggregates of the protein tau that modifies its characteristics becoming toxic, suggesting that tau may play role in both of these conditions. In the proposed research project, we will explore the hypothesis that TBI following shockwave exposure leads to impairments of cell-to-cell communication underlying cognitive problems in AD through a modification in the protein tau and involvement of the SUMOylation pathway, a molecular cascade that has recently been found to contribute to AD. In support of this, using electrophysiological and behavioral methods, we have found that increase in attachment of a SUMO1 group to proteins worsens cell-to-cell communication and cognition whereas increase in attachment of a SUMO2 group, a different member of the same family of proteins as SUMO1, ameliorates them. In addition, in preliminary experiments using biochemical methods to investigate SUMOylation, we have found that while attachment of SUMO2 groups is reduced in the brain of animal models of tau-induced toxicity and following TBI, SUMO1 attachment is increased. In preliminary experiments using biochemical methods to isolate tau, and both electrophysiological and behavioral assays, we also made the surprising discovery that tau extracted from the brain of shockwave exposed mice is capable of impairing both cell-to-cell communication and memory in recipient animals that were treated with it. These impairments were similar to the electrophysiological and behavioral changes produced by tau extracted from the brains of humans with AD. In the experiments outlined in this proposal, we will use similar biochemical strategies together with electrophysiological and behavioral methods to: (1) test the prediction that increased SUMO1 attachment to proteins contributes to impairments of cell-to-cell communication and cognition as well as toxic tau productions in shockwave-induced TBI; (2) test the prediction that increased SUMO2 attachment to proteins protects against abnormal cell-to-cell communication and cognition as well as toxic tau production by shockwave-induced TBI; (3) test whether the susceptibility to cognitive and behavioral impairment in shockwave-induced TBI as well as AD is associated with changes in the level of SUMOylation. The proposed research project is aligned against
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310384
Entities
People
- Ottavio Arancio
Organizations
- Columbia University
- United States Army