Decreased Levels of Beta‐Arrestin 1 in Brains of Patients with Alzheimer's Disease
Authors: Potter Pamela , Choi Sara , Jones Douglas , Beach Thomas 
Published: June 2021

Previous studies in our laboratory have shown that muscarinic receptors become uncoupled from G‐proteins in brains of patients with Alzheimer's disease (AD). Interestingly, this process began prior to the development of dementia, in that there was some degree of uncoupling in patients without cognitive impairment but who had increased levels of beta‐amyloid post‐mortem. This suggested that these patients might have been on a pathway of progression to AD, and may have represented a very early stage of the disease process. In order to further understand this process, we began to investigate levels of G protein receptor kinases and beta‐arrestin in these brain samples. These proteins are involved in trafficking of G‐protein coupled receptors, and we hypothesized that uncoupling of muscarinic receptors could be a result of altered levels of these proteins. We previously reported, using Western blot, that there was a decrease in beta‐arrestin in the brains of patients with AD1, but we were not able to differentiate between beta‐arrestin 1 and beta‐arrestin 2. Using Western blotting, we also found a loss of membrane bound GRK‐2, but no change in total GRK‐2.

In this study, we used the more quantitative analysis provided by ELISA assays to investigate levels of beta‐arrestin 1 and 2 in temporal cortex samples of patients with AD, or non‐demented controls with either a very low to zero amount of amyoid plaques (low pathology; LP), or a high amount of amyloid (high pathology; HP). Levels of total GRK‐2 and GRK‐5 were also measured.

We found a decrease in levels of beta‐arrestin 1 in the AD brains. There was some decrease in beta‐arrestin‐1 in the brains of high pathology controls, compared to those in low pathology controls. This contrasts with the increase in beta‐arrestin 1 described using Western blot in AD patients2. In contrast to the results reported by Thathiah et al3, we did not find an increase in beta‐arrestin 2 using ELISA. We previously found a trend towards an increase in beta‐arrestin 2 as levels of beta amyloid increased. It is possible that the temporal cortex is less likely to develop alterations in this protein than the entorhinal cortex and hippocampal regions, which are affected earlier in AD, and which were used in that study. In agreement with earlier results, total levels of GRK‐2 and GRK‐5 were unaffected.

In this study we describe a loss of beta‐arrestin 1 in patients with AD, with no alteration in beta‐arrestin 2 or GRK‐2 and GRK‐5. Increases in beta‐arrestin 1 may precede the development of dementia, as they begin to decrease in patients who are cognitively normal but have high levels of amyloid plaque pathology. Changes in beta‐arrestin could affect receptor function and alter processing of beta‐amyloid in AD. Our study also suggests the possibility that alterations in proteins involved in signal transduction may vary in different regions of the brain as AD develops.

Support or Funding Information

Supported by a intramural grant from Midwestern University.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.