Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive deficits including memory deficits. At the tissue level, AD is characterized by two main histological alterations: Amyloid plaques consisting of aggregated amyloid-β peptide (Aβ) and neurofibrillary tangles caused by the aggregation of hyperphosphorylated TAU protein. Neuroinflammation is another important feature of AD. The early stages of AD represent an interesting phase to target to slow the disease progression, but they are still ill-characterized. The accumulation of Aβ peptides, or amyloidosis, is an early feature of AD that occurs several years before the cognitive symptoms. Thus, Aβ-based animal models represent useful tools for studying the early phases of the disease. The main mouse models used to study AD are transgenic mice, which are based on the overexpression of human forms of APP and/or PSEN1/2 carrying mutations identified in AD patients. Such models lead to the overexpression of both Aβ and APP; their phenotype is thus biased by the overexpression of other APP degradation fragments. To overcome this problem, Dr. Saido's team developed Knock-In models, including the APPNL-F mice [1]. In this model APP is humanized, carries the Swedish (NL) and Iberian (F) mutations, but is expressed under the control of its endogenous promotor, leading to the overproduction of Aβ peptide while APP expression remains at physiological levels. Yet, information is lacking regarding the kinetics of the apparition of the AD-like alterations in this model.To better characterize this more pathophysiological model and determine the optimal window to study the early stages of the disease, we used a battery of behavioral, histological, and molecular approaches and characterized alterations in 3-, 6-, and 9-month-old mice. Learning and memory impairments were assessed using the Barnes Maze. The number of Aβ-plaques and the astro- and microglial reaction were evaluated by immunohistochemical quantification. Finally, neuroinflammation was analyzed by qPCR. In both males and females, we evaluated the impact of genotype (WT, NLF/+ and NLF/NLF) on AD key features.Our results identify the onset of mild cognitive impairment, amyloidosis and glial reaction, and reveal which age, sex and genotype are, in this model, most relevant for studying the early phase of AD.References1 Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC (2014) Single App knock-inmouse models of Alzheimer's disease. Nat Neurosci 17: 661-663 Doi 10.1038/nn.3697