Amyloid-Peptide Vaccinations Reduce β-Amyloid Plaques but Exacerbate Vascular Deposition and Inflammation in the Retina of Alzheimer’s Transgenic Mice

Department of Neurology, University of California Irvine School of Medicine, USA.
American Journal Of Pathology (Impact Factor: 4.59). 11/2009; 175(5):2099-110. DOI: 10.2353/ajpath.2009.090159
Source: PubMed


Alzheimer's disease (AD) is pathologically characterized by accumulation of beta-amyloid (Abeta) protein deposits and/or neurofibrillary tangles in association with progressive cognitive deficits. Although numerous studies have demonstrated a relationship between brain pathology and AD progression, the Alzheimer's pathological hallmarks have not been found in the AD retina. A recent report showed Abeta plaques in the retinas of APPswe/PS1DeltaE9 transgenic mice. We now report the detection of Abeta plaques with increased retinal microvascular deposition of Abeta and neuroinflammation in Tg2576 mouse retinas. The majority of Abeta-immunoreactive plaques were detected from the ganglion cell layer to the inner plexiform layer, and some plaques were observed in the outer nuclear layer, photoreceptor outer segment, and optic nerve. Hyperphosphorylated tau was labeled in the corresponding areas of the Abeta plaques in adjacent sections. Although Abeta vaccinations reduced retinal Abeta deposits, there was a marked increase in retinal microvascular Abeta deposition as well as local neuroinflammation manifested by microglial infiltration and astrogliosis linked with disruption of the retinal organization. These results provide evidence to support further investigation of the use of retinal imaging to diagnose AD and to monitor disease activity.

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Available from: Zhiqun Tan
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    • "Recent findings add to the growing evidence that ocular vasculature may be involved in AD, but only few studies have investigated this topic in vivo [45] [46]. Frost and colleagues, employing retinal photography, demonstrated vascular attenuation, increased vessel widths, reduced complexity of branching pattern, and altered branching geometry in the retina of patients with AD. "
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    ABSTRACT: Background: The involvement of retina and its vasculature has been recently described in Alzheimer's disease (AD). However, none of the previous works have yet investigated the choroid in vivo. Objective: Spectral domain optical coherence tomography (SD-OCT) and enhanced depth imaging (EDI) technique is non-invasively used to assess choroidal thickness in patients with AD and to determine whether the peripapillary retinal nerve fiber layer (RNFL) and central retinal thickness are reduced compared to normal subjects. Methods: Forty-two eyes of 21 patients (mean age, 73.1 ± 6.9 years) with a diagnosis of mild to moderate AD and 42 eyes of 21 age-matched control subjects (mean age, 70.3 ± 7.3 years) were included in this prospective, cross-sectional study. All the subjects underwent neuropsychological (MMSE, ADAS-Cog, and CDR) and ophthalmological evaluation. The SD-OCT images of the choroid were obtained by EDI modality. Choroidal thickness was measured by manual segmentation. The following parameters, measured automatically by the OCT software, were also analyzed for each eye: 1-mm central subfield (CSF) retinal thickness, peripapillary RNFL thickness. Results: Choroidal thickness was significantly thinner in AD than in control eyes (p < 0.05). No difference in CSF retinal thickness was found between groups (p > 0.05). Mean peripapillary RNFL thickness in all four quadrants was similar between groups (p > 0.05). OCT measurements were not correlated with any of the tested psychometric parameters (p > 0.05). Conclusion: Compared with healthy subjects, patients with AD showed a significant reduction in choroidal thickness. Choroidal thinning may represent an adjunctive biomarker for the diagnosis and follow-up of this disease.
    Full-text · Article · Feb 2014 · Journal of Alzheimer's disease: JAD
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    • "We believe that this hypothesis should now be tested in the retina of transgenic AD mouse models to provide a " proof of principle " for considering altered neuronal excitability as the earliest diagnostic markers for AD. There is so far no study of transgenic AD mice retinas during the period preceding significant A␤ accumulation in spite of the retinal processing of A␤PP to A␤ and its accumulation into the A␤ plaques reported in the advanced stages of AD pathology [35] [40] [41]. "
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    ABSTRACT: Alzheimer's disease (AD) develops undiagnosed for 10-15 years due to the lack of early diagnostic biomarkers. Visual deficits are common and crippling in AD patients and histopathological alterations found in the retina and brain are similar. We hypothesize that subtle morphological and functional changes in microglial and neuronal activities, such as those recently reported in the hippocampus, may also occur in retina during the preclinical stages of AD. These alterations are likely much more accessible to modern imaging and electrophysiological exploration than those occurring in the hippocampus and therefore, may serve as the earliest diagnostic biomarkers for AD.
    Full-text · Article · Jan 2014 · Journal of Alzheimer's disease: JAD
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    • "Neurodegeneration in AD is attributed to multiple etiological factors such as cerebrovascular dysfunction [3], persistent oxidative stress [4], inflammation [5] [6], increased glycation *Address correspondence to this author at the Semantic Computing Lab, Data Analytics Department, Institute for Infocomm Research (I2R), 119613, Singapore; Tel: +65 6408 2142; Fax: +65 6776 1378; E-mail: end products [7] insulin resistance [8], apoplipoprotein E [8], mitochondrial dysfunction [9], impaired energy metabolism [10] [11] and activation of pro-death signaling pathways resulting in cell death [12] [13]. "
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