Thursday, November 21, 2024
11/21/2024
Development of Biotherapeutic Nanogels for Alzheimer’s Disease Treatment. PROJECT SUMMARY (ABSTRACT): Alzheimer's disease (AD) is a neurodegenerative disease that has affected about 44 million people worldwide. Available treatments temporarily improve the associated symptoms, such as memory loss and difficulty in thinking and reasoning. Even with the recent approvals of Aduhelm and Leqembi targeting Aβ which may benefit only a subset of patients, novel interventions based on multiple other mechanisms are still needed due to the heterogeneous nature of AD. Most importantly, AD is characterized by β amyloid (Aβ) deposition, directly linked to oxidative stress and neuroinflammation. The need is to develop therapies that target the identified biomarkers of AD, which can stop or significantly delay the progression of the disease. This proposal utilizes the patented state-of-the-art autofluorescent biopolymeric nanogels (US Patent 10, 344,100; 2019; WO/2020/247730) with inherent anti-viral properties, biodegradability, and cellular biocompatibility. These nanogels have demonstrated salient features of biocompatibility, anti-viral, stability, and cellular uptake by microglial cells and also can transmigrate across the blood-brain barrier (BBB). The preliminary molecular dynamics simulations studies of the polyol-Aβ complex obtained by docking polyol to Aβ fibril showed that polyol binds to the interface where Aβ peptides stack, potentially inhibiting the Aβ formation. Given these findings, we hypothesize that the increased content of polyol and decreased polydispersity index of the nanogels will significantly increase the transport of nanogels across the BBB. The linseed polyol will play a significant role in inhibiting the growth of β amyloid (Aβ) aggregates, and the nanogels will be used to target the identified biomarkers of AD-like amyloid β, neurofibrillary tangles as well as inflammatory markers such as tumor necrosis factor-α (TNF-α), NLRP3 and NF-kB levels in the brain. To this end, In Specific Aim 1 we will improve our developed biotherapeutic nanogel for enhanced transmigration across the BBB and study the efficacy of the developed nanogel to ameliorate the oxidative stress in Alzheimer's disease. In Specific Aim 2, we will test the in vivo efficacy of the developed nanogel on amyloid and tau pathology as well as neuroinflammation, dendritic spines, and learning skills in a 3xTg mouse model of AD. Altogether, we propose to develop a novel nanogel system with enhanced transmigration across the BBB with more effective biotherapeutic efficacy to ameliorate oxidative stress and neuroinflammation associated with AD, which is a very important unmet clinical need, and it is an area of high priority in AD/ADRD and is within the mission of NIA. The above system will act as a multifunctional nanogel system inhibiting Aβ aggregate, and fibril formation thereby rescuing from neuroinflammation, loss of dendritic spines, and cognitive decline in AD.
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