MCH/COX2-depend regulation of neuronal function and neuroinflammation in Alzheimer’s disease

ended

Alzheimer’s disease (AD) patients stay in a prodromal phase over many years before robust cognitive decline. During this phase, complex molecular events lead to cellular alterations, resulting in aberrant synaptic activity and chronic inflammation which leads to neuronal death and cognitive impairment. My unpublished work, shows that melanin-concentrating hormone (MCH) regulates synaptic function and revealed that the MCH system is impaired in a mouse model of early AD and AD patients. I showed that MCH regulates the neuronal expression of multiple immediate early genes that control neuronal activity, and more interestingly the expression of Ptgs2/COX2. COX2 catalyzes the formation of pro-inflammatory prostaglandins from arachidonic acid but upon activity change it produces specialized pro-resolving mediators. Thus, precise COX2 levels and activity are essential to regulate the synthesis of bioactive lipids involved in the initiation and arrest of inflammation. Ptgs2/COX2 is expressed in excitatory neurons and a link to synaptic function, seizure and neuroinflammation-associated to seizure has been established. My preliminary data shows that excitatory neurons from a mouse model of early AD that displays MCH-system dysfunction, aberrant synaptic activity and neuroinflammation have altered Ptgs2 expression. Together with genetic studies that place lipid metabolism as a mediator of microglia-mediated neuroinflammation, this suggest that COX2 can play a critical role in the neuron-microglia interaction during the prodromal phase of AD. I hypothesize that impaired MCH system leads to aberrant neuronal activity and increased Ptgs2 expression, increasing pro-inflammatory mediators and recruiting microglia activation. Here, I will study how MCH-system/Ptgs2 interaction affects neuronal lipid metabolism and test if it regulates neuron-microglia communication contributing to neuroinflammation and to the onset of cognitive decline.