Abstract
BackgroundBeyond cognitive decline, Alzheimer’s disease (AD) is characterized by numerous neuropathological changes in the brain. Although animal models generally do not fully reflect the broad spectrum of disease-specific alterations, the APPSL mouse model is well known to display early plaque formation and to exhibit spatial learning and memory deficits. However, important neuropathological features, such as neuroinflammation and lipid peroxidation, and their progression over age, have not yet been described in this AD mouse model.MethodsHippocampal and neocortical tissues of APPSL mice at different ages were evaluated. One hemisphere from each mouse was examined for micro- and astrogliosis as well as concomitant plaque load. The other hemisphere was evaluated for lipid peroxidation (quantified by a thiobarbituric acid reactive substances (TBARS) assay), changes in Aβ abundance (Aβ38, Aβ40 and Aβ42 analyses), as well as determination of aggregated Aβ content (Amorfix A4 assay). Finally, correlation analyses were performed to illustrate the time-dependent correlation between neuroinflammation and Aβ load (soluble, insoluble, fibrils), or lipid peroxidation, respectively.ResultsAs is consistent with previous findings, neuroinflammation starts early and shows strong progression over age in the APPSL mouse model. An analyses of concomitant Aβ load and plaque deposition revealed a similar progression, and high correlations between neuroinflammation markers and soluble or insoluble Aβ or fibrillar amyloid plaque loads were observed. Lipid peroxidation, as measured by TBARS levels, correlates well with neuroinflammation in the neocortex but not the hippocampus. The hippocampal lipid peroxidation correlated strongly with the increase of LOC positive fiber load, whereas neocortical TBARS levels were unrelated to amyloidosis.ConclusionsThese data illustrate for the first time the progression of major AD related neuropathological features other than plaque load in the APPSL mouse model. Specifically, we demonstrate that microgliosis and astrocytosis are prominent aspects of this AD mouse model. The strong correlation of neuroinflammation with amyloid burden and lipid peroxidation underlines the importance of these pathological factors for the development of AD. The new finding of a different relation of lipid peroxidation in the hippocampus and neocortical regions show that the model might contribute to the understanding of complex pathological mechanisms and their interplay in AD.
Highlights
Beyond cognitive decline, Alzheimer’s disease (AD) is characterized by numerous neuropathological changes in the brain
All Amyloid beta (Aβ) levels were very low in non-transgenic mice at 6 months and increased only moderately until 12 months of age (Figure 1A)
From the correlation data presented in this study we demonstrate that most measured variables increase in parallel which makes it impossible to incriminate one variable as the source, at least for the APPSL mouse model
Summary
Alzheimer’s disease (AD) is characterized by numerous neuropathological changes in the brain. Alzheimer’s disease (AD) is characterized by various neuropathological events including amyloid plaques, oxidative stress, and neuroinflammation. Dysregulated amyloid precursor protein (APP) metabolism and resulting Aβ generation seem to be central and early events in the disease [1]. Activated microglia and reactive astrocytes represent the pivotal pathological hallmarks of neuroinflammation. Microgliosis is well known to be activated by Aβ, Aβ fibrils, and Aβ oligomers and occurs early in AD [2,3,4,5]. Neuroinflammation promotes further Aβ expression and oxidative stress. Co-occurrence of neuroinflammation and oxidative stress markers leads to enhanced Aβ generation [13], closing the circuit between reciprocal interferences of neuropathological changes in AD
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