An evaluation of progressive amyloidogenic and pro-inflammatory change in the primary visual cortex and retina in Alzheimer's disease (AD)

P3‐117: Progressive Inflammatory Pathology in the Retina of Aluminum‐Fed 5XFAD Transgenic Mice

“…The use of humanized murine Tg-AD models has significantly increased our understanding of the role of the pathological mechanisms that drive amyloidogenesis and inflammatory degeneration characteristic of the AD phenotype [6][7][8][9][10]. In the AD brain Aβ42 peptides progressively accumulate and self-aggregate, evolving into higher order proinflammatory senile plaque deposits; in progressive neurodegenerative diseases of the retina such as agerelated macular degeneration (AMD), Aβ42 peptides accumulate with age and selfaggregate into highly insoluble pro-inflammatory lesions called drusen [27][28][29][30][31][32].…”

“…Elevations in CRP (P02741; also known as pentraxin 1; MW~25.1 kDa), a highly soluble serum protein and sensitive biomarker for systemic inflammatory disease, has recently been shown to promote Aβ42 peptide production and amyloidogenesis [30,31]. The parallel and coordinated up-regulation of Aβ40 and Aβ42 peptides, COX-2 and CRP in aluminum-treated 5xFAD animals implicates an aluminum-orchestrated increase of pro-inflammatory signaling in both the brain cortex and retina of 5xFAD mice [3][4][5][6]. Indeed multiple previous studies have shown that aluminum exerts significant pro-inflammatory effects in a variety of embryologically-related cell types of the mammalian CNS [4,[10][11][12][13][14][15][16][17]25,32,33].…”

“…There is very recent evidence that AD involves not only the brain's limbic system, but primary visual cortical regions, the thalamus, and eventually the sensory retinal ganglia, especially in as AD progresses into its later stages [2][3][4][5][6][7][8]. Interestingly, the anatomical linkage from the brain's limbic system to the primary visual cortex, to the thalamus, and from the thalamus to the retinal ganglion of the posterior retina can involve as few as three neurons and their processes [6,27,28,31,32,34]. The current results further suggest that in Tg-AD models which are genetically predisposed to developing AD-type amyloidogenesis, that aluminum not only accelerates AD-type brain pathology but that other primary sensory organs such as the retina of the eye are also affected.…”

“…Age-matched control and 5xFAD brain and/or retina at 0, 1.5, 3 and 5 months were analyzed for Aβ40 and Aβ42 peptide and COX-2 and CRP protein levels using ELISA and Western analysis [3,[5][6][7][8]. Further details on the quality control for these 5xFAD brain and retinal samples, sample handling and analysis have been recently published [3,[18][19][20][21].…”

“…Out of multiple Tg-AD models studied by our laboratory (Tg2576, PSAPP, 3xTg-AD, etc.,) the 5xFAD model exhibits the most rapid and prolific accumulation of Aβ42 peptides in the brain and retina of any Tg-AD animal studied to date [2][3][4]. Whether amyloidogenesis originates independently in the brain and retina, or whether amyloidogenic signals originate in the brain and spread via the primary visual cortex and thalamus to the retina is open to question, but current data now favor the latter possibility [4][5][6][7][8]. Several laboratories have independently studied the effects of supplementing the diets of amyloidoverexpressing Tg-AD murine models (Tg-2576, APP/PS1, 5xFAD, etc.,) with aluminum (as chloride, lactate, maltolate or sulfate) and have evaluated the impact of ingested aluminum with pathological outcome [9][10][11][12][13][14][15][16][17].…”