Mitigation of Aβ 25-35 -Induced Cognitive Deficits in C57BL/6 Mice via Thermal Cycling Stimulation Employing Focused Ultrasound

Hyperthermia (HT) is recognized across various medical disciplines for its capacity to modulate specific protein expressions. In efforts to improve Alzheimer’s disease (AD), HT has the potential to regulate heat shock proteins (HSPs) and antioxidant enzymes, which helps decrease the aberrant accumulation of β-amyloid (Aβ) protein and oxidative stress. Nonetheless, the precise delivery of mild hyperthermia to the brain remains a significant challenge. To apply mild hyperthermia targeted to the brain and evaluate its impact on cognitive improvement, this study used focused ultrasound (FUS) to administer localized mild hyperthermia to the brains of AD mouse induced by intracerebroventricular (i.c.v.) injection of Aβ 25-35 . For considerations of safety and therapeutic efficacy, a thermal cycling-hyperthermia (TC-HT) protocol was adapted into a focused ultrasound-mediated thermal cycling stimulation (FUS-TCS), which was compared with the continuous focused ultrasound-mediated hyperthermia stimulation (FUS-HTS). The findings revealed that the FUS-TCS treatment group exhibited a significant improvement in cognitive performance, as evidenced by enhanced outcomes in the Y-maze and novel object recognition (NOR) tests. Furthermore, this group demonstrated increased expression of Aβ-degrading enzymes and antioxidant proteins, including heat shock protein 70 (HSP70), neprilysin (NEP), insulin degrading enzyme (IDE), sirtuin 1 (SIRT1), and superoxide dismutase 2 (SOD2). These results suggest that localized mild hyperthermia targeting the brain using FUS-TCS treatment represents a promising strategy for ameliorating cognitive deficits associated with AD.