The link between Alzheimer’s disease and primary open-angle glaucoma


Paul Knepper






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Purpose: Alzheimer’s disease (AD) and primary open-angle glaucoma (POAG) are common and devastating neurodegenerative diseases without known causes. While the buildup of beta-amyloid (Aβ) plaques in the brain is widely believed to be the central event in AD pathology, recent evidence suggests that Aβ is also linked to POAG and age-related macular degeneration. The underlying hypothesis of one protein, i.e., Aβ, causing AD, POAG, and age- related macular degeneration suggests that the common denominator is Aβ-induced pathology. In this chapter, we review several overlapping Aβ-associated microvascular abnormalities that our laboratory has found in both POAG and AD patients, including increased coagulation capillary abnormalities.
Methods: Blood was collected via venipuncture from control, POAG, and AD subjects and several in-vitro
assays were performed. Superactivated platelets (SAPs) were produced by stimulation with thrombin and convulxin and identified by flow cytometry using fluorophore conjugated antibodies CD41-PE to identify platelets, PAC-1-FITC to identify activated platelets, and biotinylated fibrinogen/streptavidin-APC to identify SAPs. Plasma viscosity was measured using a cone-plate rheometer at low shear with and without thrombin and convulxin. Nailfold capillary microscopy was used to examine the nailfold capillaries of POAG and AD patients. In addition, an angiogenesis assay was used to determine the toxicity of Aβ fragments and sCD44v6 to human umbilical vein endothelial cells.
Results: SAPs are characterized by a negatively charged, phosphatidylserine-rich outer membrane and the
selective release of alpha-granules, resulting in the amplification of the coagulation cascade. POAG patient SAP levels were 52.24% and AD patient SAP levels were 49.9%, which were each highly significant compared to control subjects (30.9%, p < 0.0001). Plasma viscosity of POAG patients was affected by a significantly lower dose of thrombin compared to controls (p = 0.005). AD patients were significantly more responsive to Aβ compared to controls subjects (p = 0.049). Both POAG and AD patients exhibited increased capillary hemorrhages compared with control subjects (p < 0.001). In the angiogenesis assay, exogenous Aβ and sCD44v6 were each toxic to endothelial cells, resulting in reduced capillary formation.
Conclusions: AD and POAG are associated with overlapping microvascular abnormalities including increased SAPs, plasma viscosity sensitivity, and capillary hemorrhages. Although the exact function of SAPs is unclear in AD and POAG, they are procoagulant and cause blood clots that can lead to the microvascular pathologies observed in the early stages of AD and POAG including vessel occlusion, reduced cerebral blood flow, and neuroinflammation. Blood-derived Aβ may facilitate this process by binding to and activating platelets, which also serve as sentinels of the innate immune system by recognizing damage-as sociated molecular patterns (DAMPs) such as Aβ, low molecular hyaluronic acid, and iron nanoparticles. In both functions, platelets are the immediate stop gap correction measure to prevent bleeding and damage. A consequence of platelets binding to DAMPs is collateral damage that occurs as Aβ is deposited by SAPs at the site of injury. These factors may help to explain the microvascular similarities between POAG and AD.

Glaucoma Research 2018-2020, pp. 175-188 #13
Edited by: John R. Samples and Paul A. Knepper
© Kugler Publications, Amsterdam, The Netherlands

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