O2–05–03: Stable trimeric A‐beta peptides: Potential vaccine immunogens to prevent ADDL‐triggered memory deficits
Year: 2007
Type: article
Abstract: The picture of Alzheimer's disease has changed dramatically over the past decade, as emerging data now implicate amyloid β-derived diffusible ligands (ADDLs) as the key memory-compromising molecules responsible for AD. We now understand that ADDLs assemble from elevated Aβ42, and they selectively attack dendritic spine receptors on a subset of neurons. The ensuing signals disrupt long-term potentiation (LTP), leading to compromised learning and memory. In connection with our collaborative ADDL-directed therapeutic antibody program, we developed novel trimeric Aβ peptide immunogens capable of generating antibodies with potent ADDL assembly blocking activity. This study targets the design and pre-clinical development of trimeric vaccine immunogens that trigger production of selective ADDL assembly-blocking antibodies, without accompanying anti-monomer or anti-fibril antibodies. We have deployed molecular dynamics and 2D NMR studies to reveal key structural aspects of stable Aβ analog trimers, allowing design of vaccine immunogens with optimized properties. Several novel trimeric immunogens are capable of triggering polyclonal antibodies with potent ADDL assembly blocking activity and minimal anti-monomer activity. Studies are continuing to generate an optimized IND-candidate immunogen. We have demonstrated the feasibility of generating vaccine immunogens that generate a trimer-specific, ADDL assembly blocking immune response. We believe that vaccines targeting Aβ trimers will be highly effective AD therapeutics with great potential to prevent AD.
Source: Alzheimer s & Dementia
Author: Grant A. Krafft
Institution: Acumen Pharmaceuticals (United States)
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2073370132