Pockes, Steffen and Walters, Michael A. and Ashe, Karen H. (2023) Targeting caspase-2 interactions with tau in Alzheimer's disease and related dementias. TRANSLATIONAL RESEARCH, 254. pp. 34-40. ISSN 1931-5244, 1878-1810
Full text not available from this repository. (Request a copy)Abstract
Targeting amyloid-fl plaques and tau tangles has failed to provide effective treatments for Alzheimer's disease and related dementias (ADRD). A more fruitful pathway to ADRD therapeutics may be the development of therapies that target common signaling pathways that disrupt synaptic connections and impede communication between neurons. In this review, we present our characterization of a signaling pathway common to several neurological diseases featuring dementia including Alzheimer's disease, frontotemporal dementia, Lewy body dementia, and Huntington's disease. This signaling pathway features the cleavage of tau by caspase-2 (Casp2) yielding Delta tau314 (Casp2/tau/Delta tau314). Through a not yet fully delineated mechanism, Delta tau314 catalyzes the mislocalization and accumulation of tau to dendritic spines leading to the internalization of AMPA receptors and the concomitant weakening of synaptic transmission. Here, we review the accumulated evidence supporting Casp2 as a druggable target and its importance in ADRD. Additionally, we provide a brief overview of our initial medicinal chemistry explorations aimed at the preparation of novel, brain penetrant Casp2 inhibitors. We anticipate that this review will spark broader interest in Casp2 as a target for restoring synaptic dysfunction in ADRD.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TUMOR SUPPRESSION; DRUG DISCOVERY; AMYLOID-BETA; CLEAVAGE; APOPTOSIS; PROTEIN; MEMORY; DEATH; DEFICIENCY; ACTIVATION |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 01 Feb 2024 11:15 |
| Last Modified: | 01 Feb 2024 11:15 |
| URI: | https://pred.uni-regensburg.de/id/eprint/59660 |
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