Abstract
INTRODUCTION
Amyloid beta oligomers (Aβos) are toxic to synapses and key to the progression of Alzheimer’s disease (AD) and amyloid pathology, representing a target for therapeutic strategies.
METHODS
Amyloid and small ubiquitin modifier 2 (SUMO2) transgenics were analyzed by electrophysiology and behavioral testing. A recombinant analogue of SUMO2, SBT02, was generated and assessed for brain penetration and the ability to mitigate amyloid pathology.
RESULTS
Elevated SUMO2 expression prevents cognitive and synaptic impairment in a mouse model of AD amyloid pathology. Systemic administration of SBT02 resulted in high brain bioavailability and prophylactically halted the progression of AD-associated deficits. SBT02 also restored cognition and synaptic function in late-stage amyloid load. Mechanistically, SUMO2 and SBT02 do not alter amyloid processing or clearance and mitigate synaptotoxicity in the presence of high amyloid loads.
DISCUSSION
SBT02 is a promising therapeutic strategy to counteract and reverse the toxic effects of Aβos in AD.
Highlights
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.
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This post is Copyright: Luana Fioriti,
Nadeeja Wijesekara,
Elentina K. Argyrousi,
Shinsuke Matsuzaki,
Hironori Takamura,
Kanayo Satoh,
Kyung Han,
Hiroto Yamauchi,
Agnieszka Staniszewski,
Erica Acquarone,
Franca Orsini,
Annacarla Martucci,
Taiichi Katayama,
Ottavio Arancio,
Paul E. Fraser | March 6, 2025