Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in an Alzheimer's disease mouse model.

Background: Cognitive decline in Alzheimer's disease (AD) is associated with hyperphosphorylated tau (pTau) propagation between neurons along synaptically connected networks, in part via extracellular vesicles (EVs). EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2 (nSMase2)-mediated cleavage of sphingomyelin. We report, for the first time, that human tau expression elevates brain ceramides and nSMase2 activity.

Inhibiting tau-induced elevated nSMase2 activity and ceramides is therapeutic in murine Alzheimer's disease.

Background: Cognitive decline in Alzheimer's disease (AD) is associated with prion-like tau propagation between neurons along synaptically connected networks, in part via extracellular vesicles (EV). EV biogenesis is triggered by ceramide enrichment at the plasma membrane from neutral sphingomyelinase2(nSMase2)-mediated cleavage of sphingomyelin. We report, for the first time, that tau expression triggers an elevation in brain ceramides and nSMase2 activity.

Dendrimer-Conjugated nSMase2 Inhibitor Reduces Tau Propagation in Mice.

Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid-β and hyperphosphorylated tau (pTau), which can spread throughout the brain via extracellular vesicles (EVs). Membrane ceramide enrichment regulated by the enzyme neutral sphingomyelinase 2 (nSMase2) is a critical component of at least one EV biogenesis pathway. Our group recently identified 2,6-Dimethoxy-4-(5-Phenyl-4-Thiophen-2-yl-1H-Imidazol-2-yl)-Phenol (DPTIP), the most potent (30 nM) and selective inhibitor of nSMase2 reported to date.

Glutamine antagonist JHU083 improves psychosocial behavior and sleep deficits in EcoHIV-infected mice.

Combined antiretroviral therapy ushered an era of survivable HIV infection in which people living with HIV (PLH) conduct normal life activities and enjoy measurably extended lifespans. However, despite viral control, PLH often experience a variety of cognitive, emotional, and physical phenotypes that diminish their quality of life, including cognitive impairment, depression, and sleep disruption. Recently, accumulating evidence has linked persistent CNS immune activation to the overproduction of glutamate and upregulation of glutaminase (GLS) activity, particularly in microglial cells, driving glutamatergic imbalance with neurological consequences.

Neutral sphingomyelinase 2 inhibition attenuates extracellular vesicle release and improves neurobehavioral deficits in murine HIV.

People living with HIV (PLH) have significantly higher rates of cognitive impairment (CI) and major depressive disorder (MDD) versus the general population. The enzyme neutral sphingomyelinase 2 (nSMase2) is involved in the biogenesis of ceramide and extracellular vesicles (EVs), both of which are dysregulated in PLH, CI, and MDD. Here we evaluated EcoHIV-infected mice for behavioral abnormalities relevant to depression and cognition deficits, and assessed the behavioral and biochemical effects of nSMase2 inhibition.