How amyloid-beta peptide and tau protein demonstrate degeneration

Aggregation of amyloid-beta (Aβ) peptide and tau protein dysregulation are implicated in Alzheimer disease, but based on a recent review, their devastating effects are apparent in myriad other neurodegenerative disorders and systemic diseases.¹

First author Morteza Abyadeh, PhD, from ProGene Technologies Pty Ltd., Sydney, Australia, and colleagues discuss the physiologic role of Aβ and tau proteins, mechanisms underlying their accumulation, and pathogenesis in cardiovascular diseases, cerebral amyloid angiopathy, stroke, cancer, diabetes, Parkinson disease and traumatic brain injury.

For the purposes of this report, in the eye, the proteins have been linked to retinal neurodegenerative diseases like glaucoma and age-related macular degeneration (AMD).

Retinal disorders

Aβ peptide.The following changes were reported to be especially prominent in glaucoma and AMD. Aging results in extracellular deposits associated with degenerative pathology such as drusen and senile plaques, respectively, in the retina and the central nervous system.² Aβ accumulation affects the retina in various neurodegenerative disorders. Studies of patients with early Alzheimer disease have reported visual impairment and retinal Aβ deposits even before significant neurodegeneration was observed.^3,4

Aβ is produced in the retinal ganglion cells (RGCs), which along with the retinal pigment epithelium (RPE) monolayer and other retinal neurons, may be the main sources of Aβ generation and secretion.⁵ Retinal Aβ levels increase with aging in mouse models.^2,6 Increased accumulation of Aβ in the RPE-Bruch membrane interface and retinal/choroidal blood vessels and decreased blood flow have been reported in C57BL/6 mice with aging.^7,8

“A pathological role of Aβ has been reported in AMD and glaucoma, which share many pathological events with Alzheimer disease, including oxidative stress and neuroinflammation. Furthermore, increased levels of Aβ have been observed in the retina of patients with Alzheimer disease.^9-12”

The three diseases are age related, and epidemiologic studies have suggested a higher risk of Alzheimer disease in patients with AMD and glaucoma.^13,14

In glaucoma, irreversible vision loss is associated with RGC death.While elevated intraocular pressure is recognised as the main trigger for RGC death, the underlying mechanism is multifactorial and unclear.¹⁵ In a rat model of glaucoma, chronic ocular hypertension increased caspase-3 and caspase-8 activation leading to abnormal amyloid precursor protein processing and increased Aβ levels, key to pressure-induced RGC death. Treatment with Aβ antibodies significantly reduced RGC apoptosis.¹⁶ Moreover, β-secretase inhibitors were neuroprotective against glutamate-induced RGC death in vitro and retinal damage induced by optic nerve crush in vivo.¹⁷ Aβ also disrupts microvilli, tight junctions, and adhesion of the RPE cells.¹⁸

Aβ40 and Aβ42 are involved in retinal inflammation, which highlights the importance of inflammation in all age-related diseases. RPE, neuroretina and vitreous analyses of mice and rats treated with intravitreal Aβ injections had overexpressed inflammation cytokines including interleukin (IL)-6, tumor necrosis factor-α, IL-1β, IL-18, caspase-1, NLRP3, and XAF1, microglia activation and ultimately RGC loss, possibly by binding to microglial scavenger receptor CD36, TLR4 and NF-κB signaling pathways.^19-22

Image credit: ©fotogurmespb – stock.adobe.com

Tau protein. Investigations into tau involvement are limited in AMD and glaucoma.

Tau protein is expressed in RGCs; however, higher protein levels are found in the axons of developing RGCs. Tau protein is critical to axon development and RGC survival.²³ Abnormal tau deposition and the presence of phosphorylated tau (p-tau) were observed in retinas of patients with uncontrolled primary and secondary open-angle glaucoma compared with healthy controls, and normal tau was found in the retina of healthy controls but not patients with glaucoma.^24,25 Elevated p-tau levels were observed in the lateral geniculate nucleus of the monkey model of glaucoma following increased intraocular pressure.²⁶ Interestingly, an in vivo rat model study showed hyper- and hypo-phosphorylation of tau protein and mislocalisation of tau protein in the somatodendritic compartment of the RGCs but not axons. Subsequent tau downregulation by short interfering ribonucleic acid (RNA) resulted in increased RGC survival, confirming the toxicity of tau protein.²⁷ Further results suggested the potential role of tauopathy in impaired autophagy and RGC death after optic nerve crush, which can be ameliorated by silencing the tau gene via short interfering RNA.²⁸ In rat RGCs, aggregation of tau protein impaired anterograde axonal transport and transportation of mitochondria by kinesin-like motors toward the cell periphery, leading to deficient energy production and accumulation of reactive oxygen species.^23,29 Tau protein also interacts with the C-terminus of the P150 subunit of the dynactin complex. Moreover, the tau protein enhanced the binding of the dynactin complex to microtubules and co-localised with dynactin. Therefore the abnormal distribution of tau in RGCs can result in dynactin mislocalisation in axons, leading to neurodegeneration.^23,30

The investigators explained that regarding the potential of Aβ peptide and tau protein as diagnostic and therapeutic biomarkers, further research is needed. While Aβ and tau have been extensively studied in the context of Alzheimer disease, their use as biomarkers in other diseases is still being explored. It is important to consider the specificity and sensitivity of these biomarkers in different conditions, as well as their correlation with disease progression and response to treatment.

“Overall, the presence of Aβ and tau protein alterations in diseases beyond Alzheimer disease suggests shared mechanisms and potential contributions to pathogenesis. Further research is necessary to unravel the specific roles of these proteins in different conditions, assess their diagnostic value, and explore their potential as therapeutic targets,” the authors concluded.

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