Gregory_2025_Neural.Regen.Res_20_2585

Alzheimer's disease (AD) and Alzheimers disease-related dementias (ADRD) represent a significant public health challenge, with projections indicating a substantial increase in affected individuals due to the aging global population. From the World Health Organization, AD/ADRD has affected more than 55 million individuals worldwide, with an additional 10 million cases diagnosed each year. According to the latest data from the Alzheimer's Association, in the United States alone, AD/ADRD has already affected millions of individuals over the age of 65 years; this number is expected to double by 2060. In 2023, total payments in the US for AD/ADRD individuals aged 65 and older amounted to $345 billion. The global cost of dementia care amounts to 1.3 trillion US dollars annually. Despite these impacts, AD/ADRD remains without a cure. The Food and Drug Administration-approved treatments have primarily addressed amyloid-beta (A) buildup (aducanumab and lecanemab), cholinesterase inhibition (donepezil, rivastigmine, and galantamine), and glutamate regulation (memantine) or its combination with donepezil. Yet, none of these Food and Drug Administration-approved treatments focus on targeting cerebral vascular pathological changes that are often associated with AD/ADRD (Fang et al., 2022). Recent studies in human and animal models have repeatedly demonstrated that reduced cerebral blood flow (CBF) is one of the causal factors contributing to the development of AD/ADRD. Cerebrovascular dysfunction, stemming from compromised CBF autoregulation, bloodbrain barrier damage, and neurovascular uncoupling, plays a critical role in promoting brain hypoperfusion (Fan and Roman, 2021). This reduction in brain perfusion precedes A and tau abnormalities, initiating AD/ADRD-related neuronal damage (Fang et al., 2023b). Inflammation is intricately linked to cerebrovascular dysfunction in AD, involving diverse mechanisms and phenotypes. Furthermore, brain hypoperfusion significantly contributes to cognitive impairment and dementia in individuals affected by AD/ADRD, particularly those with prevalent risk factors such as hypertension and diabetes mellitus (DM) (Wang et al., 2020, 2022). Soluble epoxide hydrolase (sEH) is an enzyme responsible for converting arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs) and linoleic acidderived epoxyoctadecenoic acids (EpOMEs) to dihydroxyoctadecenoic acids (DiHOMEs). The brain is rich in AA, governing various functions, including inflammation, which is expected to play a role in AD/ADRD. Despite its reputation for generating pro-inflammatory substances, AA can also produce epoxy fatty acids, which serve crucial anti-inflammatory functions, maintaining equilibrium alongside its classical products. Human studies have provided compelling genetic evidence linking single nucleotide polymorphisms of EPHX2, the gene encoding sEH, to cardiovascular, renal, and neurodegenerative diseases, including AD/ADRD. These findings implicate various pathways, including amyloid processing, inflammation, neuromodulation, metabolism, and vasculature regulation, in the pathogenesis of AD/ADRD (Ghosh et al., 2020; Tang et al., 2023). The sEH enzyme is widely distributed in the brain and is found in neurons, glial cells, vascular smooth muscle cells (VSMCs), and endothelial cells. Both AA and linoleic acid are released from the cell membrane by phospholipase A2 (PLA2), with elevated levels of PLA2, epoxy fatty acids, and sEH observed in AD/ADRD animals and patients. Increased PLA2 levels in AD/ADRD and traumatic brain injury have been linked to reduced endothelial inward rectifier potassium 2 (Kir2.1) activity by lowering phosphatidylinositol bisphosphate levels (Sackheim et al., 2021). A recent study by Fang et al. (2023a) revealed that A buildup is associated with reduced expression of cerebral capillary endothelial Kir2.1 and neurovascular uncoupling in a rat model of AD. Furthermore, alterations in oxylipins, such as changes in EET levels, elevated ratios of DHETs/EETs, and DiHOMEs/EpOMEs, have been observed in AD mice and ADRD patients. EETs play a role in reducing inflammation and serve as endothelial-derived hyperpolarizing factors until they are converted to DHETs by sEH. DiHOMEs, furthermore are markers and contributors to tissue inflammation in various diseases (Hammock et al., 2021). Genetic deletion or inhibition of sEH has shown beneficial effects on cognition in AD and ADRD associated with DM (Ghosh et al., 2020; Tang et al., 2023). Ghosh et al. (2020) reported that 1-(1-Propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU), a specific small-molecule sEH inhibitor, restored microglia and astrocyte reactivity and improved immune function in 5FAD AD mice. The anti-inflammation effect of sEH inhibition in AD mice was associated with reduced A plaques and improved neuronal and cognitive function. Another study by Minaz et al. (2018) demonstrated that the administration of TPPU in DM-ADRD rats significantly mitigated DM-induced alteration in levels of neurotransmitters and the activity of acetylcholinesterase, reduced oxidative stress, and improved cognitive function. In addition to multiple studies showing that cognitive protection by sEH inhibition is due to the anti-inflammatory and neuronal protective effects, a most recent study by Tang et al. (2023) demonstrated that in AD (TgF344-AD) and DM-ADRD (T2DN) rats, inhibiting sEH with TPPU yielded notable improvements in the myogenic response, CBF autoregulation, and neurovascular coupling. These enhancements were correlated with improved brain perfusion and cognition, alongside reduced neurodegeneration and amyloid plaques (Tang et al., 2023). CBF autoregulation maintains consistent blood flow to meet the high energy demand in the brain, which lacks energy storage units, and safeguards capillaries from pressure changes (Wang et al., 2022). This homeostasis process acts through the interplay of VSMCs, pericytes, endothelial cells, and astrocytes. Pressure elevations trigger CBF autoregulation via VSMC myogenic response in cerebral arteries, while metabolic, neurogenic, and other local factors respond to perfusion pressure reduction, resulting in vasodilation. Poor CBF autoregulation exacerbates capillary pressure transmission, leading to blood-brain barrier leakage, glial activation, neurodegeneration, and cognitive deficits, which correlate with cerebral vascular disease, stroke, AD, hypertension, and diabetes-related ADRD (Wang et al., 2022). Neurovascular uncoupling could be a downstream consequence of impaired CBF autoregulation, also linked to brain hypoperfusion. Independent of changes in blood pressure, local neuronal stimulation enhances extracellular potassium levels and activates Kir2.1 channels activation in capillary endothelial cells, resulting in hyperpolarization and vasodilation, thus augmenting local CBF. AD rats display a disconnected neuronal activity and CBF response, failing to enhance brain perfusion with intense neuronal stimulation. In the study by Tang et al. (2023), TPPU (1 mg/kg per day in drinking water for 9 weeks) was administered to 18-month-old DM-related ADRD rats and 6-month-old TgF344-AD rats. Notably, TPPU treatment did not alter body weight, plasma glucose, or HbA1C levels; however, learning, short-term, and long-term memory dysfunction in both DM and AD rats detected by an 8-arm water maze were effectively rescued (Tang et al., 2023). Moreover, they observed that inhibiting sEH in AD/ADRD rats normalized cerebral hemodynamics, including the myogenic response of the middle cerebral artery and parenchymal arteriole, as well as the autoregulation of CBF. In isolated VSMCs from AD middle cerebral arteries, contractility was markedly reduced compared to controls. Interestingly, treatment of control cells with Abeta(1-42) led to a dose-dependent decrease in cell contractility. Moreover, diminished VSMC contractility was rescued by TPPU treatment in AD cells. Furthermore, TPPU-treated AD brains exhibited significantly reduced amyloid plaques in the cortex and hippocampus. Neuronal counts in the hippocampus increased in both TPPU-treated AD and DM-ADRD rats. This study underscores the effectiveness of chronic sEH inhibition in reversing cerebrovascular dysfunction and neurodegeneration and reducing amyloid plaques, demonstrating that this intervention successfully mitigates cognitive impairments in animal models of AD/ADRD. These collective results strongly advocate for the potential of sEH inhibition as an innovative and promising therapeutic avenue for addressing AD/ADRD.