An App knock-in rat model for Alzheimer’s disease exhibiting Aβ and tau pathologies, neuronal death and cognitive impairments

Abstract

A major obstacle in Alzheimer’s disease (AD) research is the lack of predictive and translatable animal models that reflect disease progression and drug efficacy. Transgenic mice overexpressing amyloid precursor protein (App) gene manifest non-physiological and ectopic expression of APP and its fragments in the brain, which is not observed in AD patients. The App knock-in mice circumvented some of these problems, but they do not exhibit tau pathology and neuronal death. We have generated a rat model, with three familiar App mutations and humanized Aβ sequence knocked into the rat App gene. Without altering the levels of full-length APP and other APP fragments, this model exhibits pathologies and disease progression resembling those in human patients: deposit of Aβ plaques in relevant brain regions, microglia activation and gliosis, progressive synaptic degeneration and AD-relevant cognitive deficits. Interestingly, we have observed tau pathology, neuronal apoptosis and necroptosis and brain atrophy, phenotypes rarely seen in other APP models. This App knock-in rat model may serve as a useful tool for AD research, identifying new drug targets and biomarkers, and testing therapeutics.

Task-dependent learning and memory deficits in the TgF344-AD rat model of Alzheimer’s disease: three key timepoints through middle-age in females

“…Importantly, the initial characterizations of the TgF344-AD rat model by Cohen and colleagues found no observable sex differences on the tasks assessed, and consequently, a majority of the subsequent studies on this model combined male and female rats 5 . This may account for some of the discordant behavioral findings, as previous AD rodent models have displayed sex differences in cognitive function and neuropathology 14 , 15 , and from a clinical perspective, it is well established that females are at a greater risk of developing AD compared to males 16 . Overall, using different paradigms to assess specific memory domains, combining sexes and ages, as well as a lack of statistical power to detect nuanced memory changes, likely contribute to the lack of accordance in behavioral findings.…”

MicroRNA-22-3p ameliorates Alzheimer’s disease by targeting SOX9 through the NF-κB signaling pathway in the hippocampus

“…In this study, the mouse hippocampal neuron cell line HT22 was used as a cell model, while the Aβ-induced cells were used to construct a cell model of AD. Studies have shown that Aβ caused the changes in apoptosis-related phenotypes [ 32 ]. After the treatment, the apoptosis rate of cells was significantly increased, while the expression of anti-apoptotic protein Bcl-2 was decreased and the expression of pro-apoptotic protein Bax was increased (Fig.…”

The tau oligomer antibody APNmAb005 detects early-stage pathological tau enriched at synapses and rescues neuronal loss in long-term treatments

“…3 ). In rats with amyloid precursor protein knock-in, mAb005 immunoreactivity precedes MC-1 immunoreactivity by ∼10 months ( 74 ). While MC-1 antibody is thought to recognize misfolding events occurring between pretangle formation and tangle deposition ( 75 ), mAb005 appears to recognize even earlier misfolding/oligomerization events that generate what we termed esoTau.…”