UCLA

Pathological inflammation and neurodegeneration in the central nervous system (CNS) in diseases such as multiple sclerosis (MS), Alzheimer’s Disease, stroke, and traumatic brain injury can lead to cognitive and motor impairment which have devastating effects on quality of life for patients. In addition, these diseases lead to overwhelming financial costs and increased societal burden. Currently available drugs can partially restrict inflammation, but chronic low-level inflammation contributes to accumulative neurodegeneration. There is an unmet need for a therapeutic which can both target inflammation as well as protect against neuron loss and axonopathy in the CNS. A protein called pituitary adenylate cyclase-activating polypeptide (PACAP) has reported neuroprotective and anti-inflammatory properties in several models of neurodegenerative diseases. However, the mechanisms for these actions are not clear.

In these studies, we investigated two possible mechanisms through which PACAP may act to regulate inflammation and neurodegeneration in the experimental autoimmune encephalomyelitis (EAE) model of MS. Using a conditional knockout approach, we deleted PACAP’s PAC1 receptor from catecholaminergic neurons and demonstrate that PAC1 signaling through these neurons regulates helper T cell polarization, regulatory T cell proliferation, and inflammatory cytokine secretion during disease development. This study indicates that PACAP can modulate inflammation in part by acting through catecholaminergic neurons, such as those of the sympathetic nervous system, which regulate the immune response. Furthermore, we also conditionally deleted PAC1 receptors in the retina and found that even in the absence of disease, PAC1 is important for maintaining neurons as well as their dendrites and axons in the eye. In addition, in the optic nerve, PAC1 plays a role in protecting axonal integrity as well as regulating the numbers of immune cells during optic neuritis. Finally, using a CNS-tropic adeno-associated virus viral vector, we demonstrated as a proof-of-principle that PACAP overexpression can protect against EAE. PACAP overexpression in the CNS led to delayed onset of EAE symptoms and reduced numbers of immune cells in the optic nerve. These studies further strengthen evidence implicating PACAP and its PAC1 receptor as promising targets for developing therapeutics to manipulate the inflammatory response and to protect against neuron loss and axonopathy in MS as well as other inflammatory neurodegenerative diseases.