Supporting data for "Adiponectin deficiency exacerbates cerebrovascular dysfunction in Alzheimer's disease"

<p dir="ltr">Cerebrovascular dysfunction (CVD) significantly contributes to the progression of Alzheimer’s disease (AD), with endothelial cells (ECs) crucial for cerebrovascular homeostasis. Adiponectin (APN), an adipocyte-secreted hormone, is known for its vasoprotective effects in the peripheral, as well as its anti-inflammatory, metabolic regulatory and neuroprotective functions within the central nervous system (CNS). We previously demonstrated that APN deficiency exacerbates amyloid-beta (Aβ) plaque deposition and cognitive decline in AD mice. However, its involvement in maintaining cerebrovascular integrity in AD remains insufficiently understood.</p><p dir="ltr">This research investigates the direct contribution of APN to CVD within AD pathology by: (1) evaluating the severity and progression of CVD in wildtype, 5xFAD (an AD mouse model overexpressing Aβ), APN knockout (<i>APN</i>^<em>-/-</em>), and 5xFAD;<i>APN</i>^<em>-/-</em> mice through functional and histopathological analyses; (2) identifying altered biological processes and signaling pathways in brain ECs via transcriptomic profiling; and (3) exploring the therapeutic potential of APN supplementation by assessing its effects on cerebrovascular functions in AD mouse models and primary brain ECs exposed to Aβ toxicity.</p><p dir="ltr">The results demonstrated that APN-deficient mice exhibited reduced resting cerebral blood flow (CBF), impaired neurovascular coupling (NVC), and disrupted blood-brain barrier (BBB), all characteristics features of CVD also observed in 5xFAD mice. Notably, APN-deficient 5xFAD mice displayed more severe CVD than 5xFAD mice alone. Transcriptomic profiling further indicated that APN deficiency independently drove AD-like genetic dysregulation in ECs, characterized by inflammatory activation and metabolic suppression. In addition, APN deficiency amplified endothelial dysfunction in AD through downregulation of pathways critical for EC survival, BBB maintenance, and neurovascular integrity. Importantly, the administration of APN restored CBF and NVC in 5xFAD mice, as well as prevented tight junction protein loss and barrier breakdown in Aβ40-exposed primary ECs.</p><p dir="ltr">These findings highlight the potential of targeting ECs with APN to alleviate CVD as a promising therapeutic strategy to delay the onset and mitigate the progression of AD. This study provides a foundation for future work aimed at identifying specific genetic and molecular biomarkers or pathways to restore APN signaling or mimic its effects within ECs, preserving cerebrovascular integrity and combating AD pathology.</p>