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bioRxiv · 10.1101/2022.01.22.477197

Glaucoma and Alzheimer: Neurodegenerative disorders show an adrenergic dysbalance

Hohberger, B.·Pruess, H. P.·Mardin, C.·Laemmer, R.·Mueller, J.·Wallukat, G.
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Abstract

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.

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Hohberger, B., Pruess, H. P., Mardin, C., Laemmer, R., Mueller, J., Wallukat, G.. 2022-01-23. Glaucoma and Alzheimer: Neurodegenerative disorders show an adrenergic dysbalance. https://doi.org/10.1101/2022.01.22.477197

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