Retinal amyloid peptides and complement factor H in transgenic models of Alzheimer's disease

Abstract

Murine transgenic models of Alzheimer’s disease (Tg-AD) have been useful to analyze the contribution of β-amyloid precursor protein (βAPP), Aβ42 peptide deposition, and the proinflammatory mechanisms that characterize Alzheimer-type neuropathology. In this report, we have studied the levels of βAPP, Aβ40 and Aβ42 peptide, as well as the innate immune and inflammatory response-regulator complement factor H in the brain and retina in four different Tg-AD models including Tg2576, PSAPP, 3xTg-AD, and 5xFAD. Aged, symptomatic 5xFAD mice showed the highest retinal abundance of Aβ42 peptides and the highest deficits in complement factor H. This may be a useful model to study the mechanisms of amyloidmediated inflammatory degeneration. The superior colliculus and retina obtained from late-stage Alzheimer’s disease revealed upregulated amyloidogenic and inflammatory signaling along the anteroposterior axis of the retinal-primary visual cortex pathway.

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

“…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].…”

“…Time points examined were 0, 1.5, 3 and 5 months; the first amyloid (Aβ peptide) pathology appears at about 1.5 months [1][2][3]. For every time point examined there were no differences in body weight or general state of health between the control and aluminum-fed 5xFAD Tg-AD animals.…”

“…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].…”

“…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]. Total brain and retinal RNA and protein were isolated using TRIzol reagent; RNA was archived for further analysis (Invitrogen, Carlsbad, CA, USA).…”

“…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]. The general consensus is that the presence of aluminum in the diets of Tg-AD murine models enhances AD-type neuropathology: (1) by up-regulating the abundance of pro-inflammatory microRNAs [3], (2) by progressively exacerbating the incidence of oxidative stress [9][10][11][12]; (3) by hastening the appearance of Aβ42 peptides, accelerating Aβ42 oligomerization, amyloidogenesis and senile plaque deposition [11][12][13]; and (4) by increasing apoptosis in brain cells that temporally correlate to deficits in memory, cognition and spatial learning [14][15][16][17], all of which are features characteristic of AD neuropathology [9][10][11][12][13][14][15][16][17]. In these experiments we studied the evolution of Aβ40 and Aβ42 peptides, and the AD-relevant pro-inflammatory biomarkers cyclooxygenase-2 (COX-2) and C-reactive protein (CRP) in the brain and retina of 5xFAD Tg-AD mice fed aluminum in their diet and age-matched controls.…”