Spatial memory deficiency early in 6xTg Alzheimer’s disease mouse model

Abstract

Alzheimer’s disease (AD) is mainly characterized by the deposition of extracellular amyloid plaques and intracellular accumulation of neurofibrillary tangles (NFTs). While the recent 5xFAD AD mouse model exhibits many AD-related phenotypes and a relatively early and aggressive amyloid β production, it does not show NFTs. Here, we developed and evaluated a novel AD mouse model (6xTg-AD, 6xTg) by crossbreeding 5xFAD mice with mice expressing mutant (P301L) tau protein (MAPT). Through behavioral and histopathological tests, we analyzed cognitive changes and neuropathology in 6xTg mice compared to their respective parental strains according to age. Spatial memory deficits occurred in 6xTg mice at 2 months of age, earlier than they occurred in 5xFAD mice. Histopathological data revealed aggressive Aβ42 and p-tau accumulation in 6xTg mice. Microglial activation occurred in the cortex and hippocampus of 6xTg mice beginning at 2 months. In 6xTg model mice, the synaptic loss was observed in the cortex from 4 months of age and in the hippocampus from 6 months of age, and neuronal loss appeared in the cortex from 4 months of age and in the hippocampus 6 months of age, earlier than it is observed in the 5xFAD and JNPL3 models. These results showed that each pathological symptom appeared much faster than in their parental animal models. In conclusion, these novel 6xTg-AD mice might be an advanced animal model for studying AD, representing a promising approach to developing effective therapy.

Idebenone Regulates Aβ and LPS-Induced Neurogliosis and Cognitive Function Through Inhibition of NLRP3 Inflammasome/IL-1β Axis Activation

“…Second, 3-month-old 5xFAD mice are a model of the early phase of AD and have not yet developed impairments of long-term cognitive ability. Spatial working memory impairment is observed in 3-month-old 5xFAD mice (72,73), but long-term spatial memory deficits are observed only in the intermediate/late phase of AD in this model, i.e., 5xFAD mice older than 6 months (74,75). Thus, future work will investigate whether idebenone improves longterm memory in 6-month-old 5xFAD mice via the Morris water maze test.…”

Long-Term Treatment of Cuban Policosanol Attenuates Abnormal Oxidative Stress and Inflammatory Response via Amyloid Plaques Reduction in 5xFAD Mice

“…To determine the effects of policosanol on microglial and astrocyte activation in 5xFAD mice, immunohistochemical analysis was performed as previously described [ 30 ]. Briefly, cryostat brain sections were washed in PBS-T (0.3% Triton X-100 in PBS), and the slices were blocked in PBS-T containing 0.5% Bovine serum albumin (BSA) and 3% normal goat serum at room temperature for 30 min.…”

Characterization of a Mouse Model of Alzheimer’s Disease Expressing Aβ4-42 and Human Mutant Tau

“…Similarly, we observed no significant increase of phosphorylated tau in PS19/ Tg4–42 hom mice except for a trend in young animals. These findings in models harboring transgenic Aβ peptides in the absence of APP overexpression strikingly contrast the obvious exacerbation of tau pathology observed in tau transgenic mice when crossed with mouse models of AD overexpressing mutant APP [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 36 ]. The overexpression of APP in the studied mouse models could be a determining factor in the exacerbation of tau pathology.…”

“…APP transgenic mice expressing the E693Δ mutation display age-dependent accumulation of intraneuronal Aβ oligomers in the absence of amyloid deposits but show abnormal tau phosphorylation from 8 months [ 6 ]. Such data is corroborated by studies from double-transgenic mouse models expressing both mutant APP and tau transgenes, showing in general increased levels of phosphorylated tau as well as accelerated tau pathology compared to their single tau transgenic parental strains [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. However, the importance of tau on the detrimental effect of Aβ is a matter of debate.…”