Grant: Project Grant

Over 771,939 Canadians live with Alzheimer's disease (AD) or other dementias. Their numbers will considerably increase in the near future. Currently, approved drugs for AD show limited effectiveness, possibly due to the inability of existing methods to detect amyloid protein clumps. Fundamental changes in AD diagnosis and therapy are urgently needed to provide comprehensive detection of all types of amyloid clumps and improve clinical therapeutic management for patient care. Our multidisciplinary team has identified a novel strategy for early diagnosis and therapy of AD based on peptide analogs called azapeptides that bind selectively to soluble amyloid protein clumps that accumulate in brain causing cell death and dementia. In animal models, our azapeptides facilitate the detection of soluble amyloid protein clumps through positron-emission tomography (PET) imaging. Our molecules are non-toxic and exhibit therapeutic potential because they can protect nerve cells by disrupting amyloid clumps and fibrils. Research is now needed to enhance their potency and biological properties to improve utility for clinical imaging and therapy. A strategic approach to generate more efficient molecules is proposed featuring the synthesis of improved structures guided by assessment of their amyloid-disrupting and cell-protecting activities, and by validation of their utility for imaging a more specific profile of AD-related amyloid clumps in clinically relevant animal models. Targeted on bioavailable, stable molecules with improved efficacy in animal models, our team will employ highly sensitive imaging techniques to conceive novel, non-invasive and predictive tools for early detection and disassembly of a range of soluble protein clump that are undetectable with existing methods. Addressing the critical need for improved diagnosis and therapy for AD patients, the proposed strategy is positioned to accelerate personalized care for patients with AD in Canada.