About This Project

Insulin and exercise improves diabetes, AD and PD. In diabetes, resident immune cells (RICs) secrete inflammatory cytokines upon ingestion of fat deposits, inhibiting Akt signaling. Glial derived neurotrophic factor (GDNF) also activates Akt. Perhaps a similar mechanism occurs in the CNS, involving RIC exposure to alpha-synuclein aggregates. We will attempt to replicate this in vitro and characterize RIC inflammatory status, then expose neuronal lines to RIC and monitor Akt inhibition.

Ask the Scientists

What is the context of this research?

Studies have suggested that dementia has a possible connection to diabetes. A major component of type 2 diabetes, RICs secrete inflammatory signals that oppose the action of insulin. Due to my experience with peripheral neurodegeneration, I was offered an opportunity to design a project focusing on central neurodegeneration. This proposal was prompted by other studies which have shown that insulin or exercise corrects peripheral diabetes and also a number of neurodegenerative insults in the CNS. Insulin or neurotrophic factors GDNF activate Akt protein. Loss of Akt activation leads to dysfunction and/or cell death peripherally and centrally, thus Akt is an essential signal of robust trophic support and vitality.

What is the significance of this project?

This study may provide evidence that inflammatory signaling can lead to a inhibition of trophic response within the CNS. Improper trophic response impairs cell function and can lead to cell death. Thus, neurotrophic factor resistance may be viewed as a novel mechanism for neurodegeneration. Therapies can be designed which enhance Akt signal or block the inflammatory signals which inhibit Akt signaling in the CNS. For example, administration of intranasal insulin improves symptoms and pathologies of PD, AD and traumatic brain injury. Lastly, RIC response to alpha-synuclein deposits (aSyn), may suggest a unifying theme for diseases of aggregation. There may be other diseases which have interstitial aggregation in common to their pathologies, a few of which are type2 diabetes, PD, and AD.

What are the goals of the project?

Alpha-synuclein (aSyn) synthetic aggregates like the aSyn deposits found in PD (PDf) or control aSyn (CTf) will be applied to a microglial cell line (uG). We expect that PDf treated uG cells to become inflammatory, and that CTf treated cells will change minimally, confirmed via measurement of inflammatory signal. Collected media from the treated uG cells will be applied to a neuronal cell line similar to the neurons which are affected in PD. Trophic signal will be measured by phospho-Akt in neuronal cells basally, or treated with glial derived neurotrophic factor (GDNF). We predict that in GDNF stimulated PDf vs CTf treated neuronal cells, the Akt response will be blunted in PDf compared to CTf uG treated neuronal cells , indicating resistance to trophic stimulus.