Inflammation, neurodegeneration and protein aggregation in the retina as ocular biomarkers for Alzheimer\u2019s disease in the 3xTg-AD mouse model

Alfonso Grimaldi,Cristina Limatola,Silvia Di Angelantonio,Carlo Brighi,Giovanna Peruzzi,Davide Ragozzino,Giancarlo Ruocco,Valentina Bonanni

doi:10.1038/s41419-018-0740-5

Abstract

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. In the pathogenesis of AD a pivotal role is played by two neurotoxic proteins that aggregate and accumulate in the central nervous system: amyloid beta and hyper-phosphorylated tau. Accumulation of extracellular amyloid beta plaques and intracellular hyper-phosphorylated tau tangles, and consequent neuronal loss begins 10–15 years before any cognitive impairment. In addition to cognitive and behavioral deficits, sensorial abnormalities have been described in AD patients and in some AD transgenic mouse models. Retina can be considered a simple model of the brain, as some pathological changes and therapeutic strategies from the brain may be observed or applicable to the retina. Here we propose new retinal biomarkers that could anticipate the AD diagnosis and help the beginning and the follow-up of possible future treatments. We analyzed retinal tissue of triple-transgenic AD mouse model (3xTg-AD) for the presence of pathological hallmarks during disease progression. We found the presence of amyloid beta plaques, tau tangles, neurodegeneration, and astrogliosis in the retinal ganglion cell layer of 3xTg-AD mice, already at pre-symptomatic stage. Moreover, retinal microglia in pre-symptomatic mice showed a ramified, anti-inflammatory phenotype which, during disease progression, switches to a pro-inflammatory, less ramified one, becoming neurotoxic. We hypothesize retina as a window through which monitor AD-related neurodegeneration process.

Highlights

Alzheimer’s disease (AD) is the most common form of dementia, accounting for 60–70% of all dementia cases
Retinal and hippocampal neuron degeneration starts at pre-symptomatic stage in 3xTg-AD mice In AD brain, the onset of neurodegenerative process and neuronal apoptosis has been linked to the caspase-3mediated cleavage of AD-linked proteins (APP and presenilins), and AD patients exhibited significant increase in synaptic procaspase-3 and active caspase-3 expression levels compared with age-matched controls[25]
By confocal immunofluorescence analysis, that cleaved caspase-3 punctate staining was present in the retinal ganglion cells (RGC) layer (Inner Layer; IL) already at five PNWs (Fig. 1a, left red dots)

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of dementia, accounting for 60–70% of all dementia cases. The main pathological and diagnostic features are the accumulation of two proteins: amyloid-β (Aβ) peptide, generated from the amyloid precursor protein (APP), which aggregates (MRI) are frequently used in the initial diagnosis of cases where cognitive AD signs are present, whereas positron emission tomographic (PET) amyloid imaging is less frequently included, mainly where confirmation is needed[6]. Official journal of the Cell Death Differentiation Association. Grimaldi et al Cell Death and Disease (2018)9:685. Besides PET amyloid imaging, cerebrospinal fluid (CSF) pathophysiological markers, including Aβ1–42, total tau, and pTau, have shown high specificity in confirming AD pathophysiology. CSF biomarkers in AD and mild cognitive impairment have been increasingly used showing that lower CSF levels of Aβ42 and higher CSF levels of total tau and pTau compared with controls were associated to severe AD7. A desirable matrix for AD biomarker detection could be through plasma, no significant differences of the concentration of Aβ markers in AD and control subjects have been found between plasma or serum[7]

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Results

Conclusion