Protein arginine methyltransferase 4 modulates nitric oxide synthase uncoupling and cerebral blood flow in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the leading cause of mortality, disability, and long‐term care burden in the United States, with women comprising the majority of AD diagnoses. While AD‐related dementia is associated with tau and amyloid beta accumulation, concurrent derangements in cerebral blood flow have been observed alongside these proteinopathies in humans and rodent models. The homeostatic production of nitric oxide synthases (NOS) becomes uncoupled in AD which leads to decreased NO‐mediated vasodilation and oxidative stress via the production of peroxynitrite (ONOO−∙) superoxide species. Here, we investigate the role of the novel protein arginine methyltransferase 4 (PRMT4) enzyme function and its downstream product asymmetric dimethyl arginine (ADMA) as it relates to NOS dysregulation and cerebral blood flow in AD. ADMA (type‐1 PRMT product) has been shown to bind NOS as a noncanonic ligand causing enzymatic dysfunction. Our results from RT‐qPCR and protein analyses suggest that aged (9−12 months) female mice bearing tau‐ and amyloid beta‐producing transgenic mutations (3xTg‐AD) express higher levels of PRMT4 in the hippocampus when compared to age‐ and sex‐matched C57BL6/J mice. In addition, we performed studies to quantify the expression and activity of different NOS isoforms. Furthermore, laser speckle contrast imaging analysis was indicative that 3xTg‐AD mice have dysfunctional NOS activity, resulting in reduced production of NO metabolites, enhanced production of free‐radical ONOO−, and decreased cerebral blood flow. Notably, the aforementioned phenomena can be reversed via pharmacologic PRMT4 inhibition. Together, these findings implicate the potential importance of PRMT4 signaling in the pathogenesis of Alzheimer's‐related cerebrovascular derangement.

The role of serum/glucocorticoid-regulated kinase 1 in brain function following cerebral ischemia

“…The number of animals per group was determined based on our previous publications 6,19 –22,26,38 –40 and power analysis with p < 0.05 (a power of 0.95) (homepage.univie.ac.at/robin.rist/samplesize.php?test=anova). We also adjusted animal numbers based on standard deviation if standard deviation was higher than projected to ensure sufficient power.…”

Amino acid metabolism in health and disease

“…216 In addition, PRMT4-catalyzed asymmetric dimethylarginine (ADMA) has been reported to bind to NOS as a ligand, leading to NOS dysfunction, resulting in decreased cerebral blood flow and aggravating AD, which can be reversed by inhibition of PRMT4. 217 Lung disease. Asthma is a variable, recurrent, long-term inflammatory disease of the respiratory tract.…”

Functional Implications of Protein Arginine Methyltransferases (PRMTs) in Neurodegenerative Diseases

“…There is evidence that the dysregulation of cerebral blood flow (CBF) in AD is related to the loss of NO signaling, a vasodilatory gasotransmitter [ 46 ]. Nitric oxide synthase (NOS), a member of the NOS family of enzymes that primarily consists of endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS), produces NO.…”

“…This faulty electron transfer has been suggested to be a contributing factor in the development of free radical species, such as peroxynitrite (ONOO−). This uncoupling process has been linked to aging in AD and in other age-related pathologies [ 46 ]. NO levels drop because of the conversion of NO to ONOO−, which in turn affects NO’s capacity to control CBF.…”

“…PRMT5 is mostly expressed in human nerve cells, and in normal conditions, it inhibits the apoptosis process by downregulating the E2F-1/p53/Bax/NF-κB/GSK-3β/Caspase 3 signaling pathway [ 49 ]. In pathological conditions, the accumulation of amyloid beta results in the inhibition of PRMT5 [ 46 ], which further potentiates the apoptosis process ( Figure 2 ).…”