Glaucoma and Alzheimer: Neurodegenerative disorders show an adrenergic dysbalance

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 ß2-adrenergic receptor (ß2-AR; i.e. agonistic autoantibodies; ß2-agAAb) and is linked to an elevated IOP and an impaired retinal microcirculation. As neurodegenerative disorder, Alzheimer's Disease (AD) is postulated to share a common molecular mechanism with glaucoma. In the present study we investigated autoimmune phenomena targeting the ß2-AR in patients with AD. Sera of the patients were analyzed in a rat cardiomyocyte bioassay for the presence of functional autoantibodies against ß2-AR. In addition, different species of amyloid beta (Aß) monomers were tested (Aß1-14, Aß10-25, Aβ10-37 Aß1-40, Aß1-42, Aβ28-40, and Aß-[Pyr]3-43). Our results demonstrate that none of the short-chain Aß (Aß1-14, Aß10-25, or Aβ28-40) showed any agonistic or inhibitory effect on ß2-AR. Contrary, long-chain Aß-[Pyr]3-43, representing a major neurogenic plaque component, exerted an activation that after blocking by the ß2-AR antagonist ICI118.551, could be identified as that the effect was realized via the ß2-AR. Moreover, the long chain Aß1-40, Aβ1-42, and Aβ10-37, yet not the short-chain Aß peptides prevented the clenbuterol induced desensitization of the ß2-AR. In addition, we identified functional autoantibodies in the sera of AD patients, activating the ß2-AR, like the ß2-agAAb found in patients with glaucoma. As autoimmune mechanisms were reportedly involved in the pathogenesis of glaucoma and Alzheimer's Disease, we postulate that overstimulation of the ß2-AR pathway can induce an adrenergic overdrive, that may play an important role in the multifactorial interplay of neurodegenerative disorders.

Fig 1. Comparison of the activity of the functional β2-adrenoceptor autoantibodies (β2-AAb) of patients with glaucoma (POAG) (n = 12) and Alzheimer’s disease (AD) (n = 11).

Both agonist-like effects were blocked by the β2-adrenoceptor antagonist ICI 118.551 (0.1μM), (p˂ 0.001). The experiments with the AAb of the AD patients were done in the presence of the α1- adrenoceptor antagonist urapidil to block the agAAb against the α1-adrenoceptor that are also present in the sera of AD patients.

Fig 2. Functional effect realized via the β2 adrenoceptor by the truncated Aβ peptide Aβ-[PYR]3–43 (n = 5): This effect was blocked by ICI 118.551 (n-4, p˂0.001), yet not by the β1 adrenoceptor antagonist bisoprolol or the α1-adrenergic antagonist urapidil.

Fig 3

Desensitization of the β2 adrenergic response by the β2-adrenergic agonist clenbuterol (a). This receptor desensitization was missed if the cells were stimulated with the β2-adrenergic AAb prepared from AD patients (b).

Fig 4

Influence of the Aβ peptides on the clenbuterol induced β2-adrenoceptor desensitization: The desensitization of the β-AR response by clenbuterol, was not influenced by the short chain Aβ peptides (a). However, the long chain Aβpeptides Aβ 10–37, Aβ1–40, and Aβ1–42 prevent the desensitization and exert a permanent stimulation of the β2-AR signal cascade (b).