Iris Publishers- Open access Journal of Ophthalmology & Vision Research | Key Transcription Factors Linking Macular Degeneration and Alzheimer’s Disease

Authored by Joseph W Eichenbaum

Alzheimer’s disease (AD) and age-related macular degeneration (AMD) have certain pathologic features in common. Chronic oxidative stress and neuroinflammation result in aggregate protein deposits, extracellular drusen in AMD, extracellular and intracellular amyloid in AD, and intracellular tau in AD, and mitochondrial proteosomal pathway damage in both. Along with risk factors: aging, smoking, hypertension, hypercholesterolemia, obesity, arteriosclerosis, unhealthy diet, chronic anticholinergic use, and latent herpetic infection, three transcription factors, NRF-2 (nuclear factor-erythroid 2) and NFKB (nuclear factor kappa B) which regulate cellular detoxification from oxidative stress and innate cellular immunity, respectively, and PGC-1α (peroxisome receptor gamma coactivator), which is the master of mitochondrial biogenesis and antioxidant control, seem to play a major role in disease progression of AMD and AD . Neuropathology and protein marker changes related to imbalances in NRF-2, NFKB, and PGC- 1α illustrate neurodegenerative and vision loses commensurate with NRF-2 and PGC-1α deficiencies and NFKB excess. Examining these transcription factors in more detail may provide insights into slowing the progression of AD and AMD. 

The global prevalence of AMD in 2020 is projected to be 196 million people [1] and that of Alzheimer’s disease was 50 million in 2017 [2]. Chronic oxidative stress and neuroinflammation from aging, injury, and individual risk factors (smoking, hypertension, arteriolosclerosis, obesity, dietary indiscretion, chronic anticholinergic use, and latent infection) in AMD and AD contribute to toxic protein deposits, loss of homeostatic protein clearance, and progressive neurodegeneration [3-11].
Neuroinflammation also provokes persistent immune response, which participates in further brain and macular damage. However, studies using anti-inflammatory therapy in AD and in AMD have yielded small, mixed or inconclusive results [12-15].
Toxic protein accumulation: in AMD, drusen, (lipoprotein deposits between the basal lamina and the retinal pigment epithelial layer, RPE) and lipofuscin (from inefficient protein clearance) [3,4,13] and in AD, extracellular and intracellular amyloid and complement and intracellular tau, (because of breakdown of the blood-brain barrier from reactive oxygen species, inflammation, or local or systemic infection), may be slow burners in chronic inflammation and its sequelae [5,6,16] However, cognitive issues, (memory and learning) in AD may precede amyloid plaque and tau fibrillar aggregates by months or longer [5]. For that matter, in AMD despite impaired lysosomal degradation, lipofuscin accumulation, defects in the ubiquitin protein clearance, and mitochondria dysfunction [3], many ophthalmologists can attest to the fact that visual loss may take years to manifest.

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