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http://dx.doi.org/10.1016/j.comtox.2024.100319 | DOI Listing |
Background: Progressive supranuclear palsy (PSP) is a devastating primary tauopathy with rapid progression to death. Although several therapies currently in the development pipeline show promising safety profiles and robust target engagement, few demonstrated significant efficacy in patients, underscoring the need to interrogate additional targets with novel therapeutic modalities to expand the potential therapeutic arsenal. To diversify the therapeutic avenues for PSP and related tauopathies (e.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
The Jackson Laboratory, Bar Harbor, ME, USA.
Background: Determining the precise genetic mechanisms that contribute to LOAD, both in coding and noncoding variants, will enable a deeper understanding of pathogenesis and advance preclinical models for the testing of targeted therapeutics.
Methods: We have introduced candidate genetic variants in the EPHA1, BIN1, CD2AP, SCIMP, KLOTHO, PTK2B, ADAMTS4, IL1RAP, IL34, and PTPRB loci into a sensitized mouse model already harboring humanized amyloid-beta, APOE4, and Trem2.R47H alleles knocked in to a C57BL/6J background.
Alzheimers Dement
December 2024
The Jackson Laboratory, Bar Harbor, ME, USA.
Background: Data from human and model organism studies suggest that genetic background influences susceptibility and resilience to Alzheimer's Disease (AD) neuropathology. We previously showed that, wild-derived PWK/PhJ (PWK) mice carrying the APP/PS1 transgene (PWK.APP/PS1) exhibit cognitive and synaptic resilience compared to traditionally-studied B6.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
National Institute on Aging, Bethesda, MD, USA.
Background: Alzheimer's disease (AD) is complex and multifactorial. Precision medicine approaches are needed to capture the basis of heterogeneity in AD pathogenesis, clinical presentation and neuropathology. Large-scale molecular, deep phenotypic and exposomal data necessary to enable precision medicine research requires team-based, interdisciplinary programs.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Institute for Memory Impairments and Neurological Disorders (MIND), Irvine, CA, USA.
Background: Alzheimer's Disease (AD) presents a significant challenge in understanding its complex pathophysiology, owing to its multifaceted genetic and environmental factors. Despite extensive research, the translatability of findings from animal models to human conditions remains a critical hurdle. This study addresses the need to uncover shared molecular changes in AD by comparing human and mouse models, thereby enhancing our understanding of the disease's underlying mechanisms and improving the prospects for effective treatments.
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