Microglia and NLRP3 Inflammasome Contribution to Nonmotor Deficits in Parkinson s Disease
Abstract
Background: Parkinson s disease (PD) is perhaps best characterized by the presentation of movement, or motor symptoms in patients. These include tremor, balance problems, and slowness of movement. A less-well described PD symptom is dementia, or impairment in thinking and memory. This is an insidious non-motor symptom; it occurs in ~20% of patients at the time of PD diagnosis, but within 20 years of diagnosis, up to ~80% of PD patients exhibit signs of memory impairment/dementia. PD dementia is the leading cause of patients being admitted to long-term care facilities. The causes behind the onset of PD dementia are not well understood, but it is thought that the accumulation of a protein called alpha-synuclein may play a crucial role in this process. Alpha-synuclein is a normal brain protein that has the tendency to form clumps or aggregates. These aggregates of alpha-synuclein have been found in the brains of PD patients. Recent advances in science have shown that this protein can spread from one brain region to the next; aggregates of alpha-synuclein can act as a toxic seed, corrupting the non-aggregated or normal alpha-synuclein in neurons/nerve cells, and spreading disease much like a virus would. When the toxic aggregates of alpha-synuclein begin to accumulate in regions of the brain responsible for thinking and memory formation, such as the cortex, it is believed that dementia and memory impairment begin to develop. Therapeutic strategies that target the spreading of alpha-synuclein are currently being evaluated as potential drug candidates for PD therapy. Many studies have shown that excess inflammation in the brain of PD patients can contribute to the progression of the disease. This brain inflammation is largely mediated by the major immune cells of the brain called microglia. Under normal conditions, microglia produce factors to promote brain health. However, under PD conditions, they switch to an activated state, producing factors that can harm neurons or nerve cells. We have previously shown that inhibiting microglial activation can promote neuron survival in PD mouse models. However, it is unknown whether microglia can contribute to the spreading of alpha-synuclein, and subsequently to PD dementia. It is also not known which signaling pathways in microglia contribute to this process. Recent work from our group has studied a complex of proteins called the Nod-Like-Receptor-Protein-3 (NLRP3) inflammasome in PD. We showed that this complex can be activated in PD. The unpublished results for this study suggest that a component of the NLRP3 inflammasome called ASC can serve as a seed that attracts alpha-synuclein, making it aggregate and spread faster. In a mouse model of alpha-synuclein spreading, excessive amounts/deposits of ASC were found in the cortex. Overall, we hypothesize that microglia contribute to the spreading of alpha-synuclein in PD via activation of the NLRP3 inflammasome. This may lead to the onset of memory disturbances in PD. Rationale/Objective 1: We will show how mice that lack the inflammasome proteins NLRP3 and ASC have reduced spreading of alpha-synuclein aggregates and reduced onset of memory problems when compared to mice that have these proteins. Rationale/Objective 2: PLX5622 is a compound that can be administered to mice through food. It selectively removes microglia from the brain. We hypothesize that mice that have fewer microglia will have lesser ASC spreading/deposits. Next, we will use molecular tools to reduce ASC levels in microglia. We will inject ASC-depleted and control mice with alpha-synuclein aggregates, which can initiate the spread of alpha-synuclein pathology, and evaluate protein aggregation and memory function in mice through well-established methods. Applicability of the Research: We seek to identify how brain inflammation contributes to dementia in PD. PD symptoms accrue over years to decades, but we propose using a mouse
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310293
Entities
People
- Nikhil Panicker
Organizations
- Cleveland Clinic
- United States Army