Genetic and pharmacologic enhancement of SUMO2 conjugation prevents and reverses cognitive impairment and synaptotoxicity in a preclinical model of Alzheimer's disease
Genetic overexpression of human SUMO2 prevents the long-term potentiation (LTP) impairments and cognitive deficits in amyloid precursor protein (APP) transgenics without affecting amyloid pathology. A recombinant analogue of human SUMO2, termed SBT02, when administered systemically, displays high brain bioavailability and has no adverse effects at high doses. Prophylactic treatment of APP transgenics with SBT02 prior to the development of amyloid pathology results in the prevention of synaptic and behavioral dysfunction. SBT02 also reverses pre-existing LTP and cognitive impairments when administered to APP transgenics with advanced and severe pathology. SBT02 has no impact on amyloid pathology, indicating a mechanism of action on synaptic resistance to Aβ toxicity.
Authors
- Paul E. Fraser (ORCID: https://orcid.org/0000-0003-1227-4239)
- Nadeeja Wijesekara (ORCID: https://orcid.org/0000-0001-5298-9779)
- Agnieszka Staniszewski
- Elentina K. Argyrousi (ORCID: https://orcid.org/0000-0003-3716-807X)
- Ottavio Arancio (ORCID: https://orcid.org/0000-0001-6335-164X)
- Erica Acquarone (ORCID: https://orcid.org/0000-0002-3266-8115)
- Taiichi Katayama (ORCID: https://orcid.org/0000-0001-8137-0481)
- Kanayo Satoh (ORCID: https://orcid.org/0009-0000-4520-2560)
- Luana Fioriti (ORCID: https://orcid.org/0000-0003-2429-8967)
- Hironori Takamura
- Franca Orsini (ORCID: https://orcid.org/0000-0001-7415-9936)
- Shinsuke Matsuzaki (ORCID: https://orcid.org/0000-0003-1786-7148)
- Kyung Ah Han (ORCID: https://orcid.org/0000-0001-6436-1938)
- Annacarla Martucci
- H. Yamauchi
Institutions
- Morinomiya University of Medical Sciences (JP)
- University of Toronto (CA)
- Mario Negri Institute for Pharmacological Research (IT)
- Occupational Cancer Research Centre (CA)
- Columbia University (US)
- The University of Osaka (JP)
Publication Details
- Journal
- Alzheimer s & Dementia
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1002/alz.70030
- Citations
- 5
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- Alzheimer's Association
- Weston Brain Institute
- National Institutes of Health
- Canadian Institutes of Health Research