Wallukat, G. | bioRxiv Science

bioRxiv2022

Glaucoma and Alzheimer: Neurodegenerative disorders show an adrenergic dysbalance

Glaucoma disease is characterized by an increased intraocular pressure (IOP), glaucomatous alterations of the optic disc and corresponding visual field defects. Even lowering the main risk factor IOP until an individual target level does not prevent this neurodegenerative disorder from proceeding. Several autoimmune mechanisms were discovered, partly showing a functionality. One of these autoimmune phenomena targets the {beta}2 adrenergic receptor ({beta}2-AR; i.e. agonistic autoantibodies; {beta}2-agAAb) and is linked to the elevated IOP and an impaired retinal microcirculation. As neurodegenerative disorder, Alzheimers Disease (AD) is postulated to share a common molecular mechanism with glaucoma. In the present study we investigated autoimmune phenomena targeting the {beta}2-AR in patients with AD. Sera of the patients were analyzed in a rat cardiomyocyte bioassay for the presence of functional autoantibodies against {beta}2-AR. In addition, different species of amyloid beta (A{beta}) monomers were tested (A{beta}1-14, A{beta}10-25, A{beta}10-37 A{beta}1-40, A{beta}1-42, A{beta}28-40, and [Pyr]-A{beta}3-42). Our results demonstrate that none of the short-chain A{beta} (A{beta}1-14, A{beta}10-25, or A{beta}28-40) showed any agonistic or inhibitory effect on {beta}2-AR. Contrary, long-chain [Pyr]-A{beta}3-42, representing a major neurogenic plaque component, exerted an activation that was blocked by the {beta}2-AR antagonist ICI118.551 indicating that the effect was realized via the {beta}2-AR. Moreover, the long chain A{beta}1-40, A{beta}1-42, and A{beta}10-37 yet not the short-chain A{beta} peptides prevented the clenbuterol induced desensitization of the {beta}2-AR. In addition, we identified functional autoantibodies in the sera of AD patients, activating the {beta}2-AR like the {beta}2-agAAb found in patients with glaucoma. As autoimmune mechanisms were reportedly involved in the pathogenesis of glaucoma and Alzheimers Disease, we postulate that overstimulation of the {beta}2-AR pathway can induce an adrenergic overdrive, that may play an important role in the multifactorial interplay of neurodegenerative disorders.

neuroscience↗

bioRxiv2019

Doberman pinschers present autoimmunity associated with functional autoantibodies: a model to study the autoimmune background of human dilated cardiomyopathy

BackgroundAutoimmunity associated with autoantibodies directed against the {beta}1-adrenergic receptor ({beta}1-AAB) is increasingly accepted as driving human dilated cardiomyopathy (DCM). Unfortunately, animal models of DCM are lacking, preventing our knowledge about {beta}1-AAB autoimmunity in DCM from being extended and hindering the development of related treatment strategies.\n\nObjectivesTo introduce an animal model, we studied Doberman pinschers, which develop cardiomyopathy (DoCM), with similarities to human DCM, with regard to their {beta}1-AAB autoimmunity.\n\nMethodsEighty-seven DP with DoCM and 31 (at enrolment) healthy controls were analyzed for {beta}1-AAB; the receptor binding site and sensitivity to inhibition were determined. In controls who developed cardiomyopathy during the follow-up, {beta}1-AAB were analyzed during the DoCM progress.\n\nResultsFifty-nine (67.8%) DoCM dogs and 19 (61.3%) controls were {beta}1-AAB positive. Excluding the 9 controls who developed DoCM in the follow-up, {beta}1-AAB positivity tended to be more pronounced in DoCM.\n\nFrom the controls who developed DoCM, 8 were {beta}1-AAB positive (p=0.044 vs. dogs remaining healthy); their {beta}1-AAB level increased with the cardiomyopathy progress. Overall mortality and mortality exclusively due to cardiac reasons during the study period, were higher (p=0.002; p=0037) in {beta}1-AAB positive dogs. The dogs {beta}1-AAB targeted a specific epitope centralized on the second extracellular receptor and were sensitive to inhibition by drugs already successful tested for the corresponding human autoantibody.\n\nConclusionsDoberman pinschers presented {beta}1-AAB associated autoimmunity similar to that driving the pathogenesis of human DCM. Consequently, DP could remove the lack of animal models available for studying {beta}1-AAB autoimmunity in DCM.

pathology↗