A Transgenic Alzheimer Rat with Plaques, Tau Pathology, Behavioral Impairment, Oligomeric Aβ, and Frank Neuronal Loss

TLDR

Alzheimer’s disease is characterized by amyloid plaques, neurofibrillary tangles, and widespread cortical neuronal loss, and the amyloid cascade hypothesis links amyloid deposition to neurotoxicity, yet existing transgenic mice fail to fully recapitulate these features. The TgF344‑AD rat fills a critical need for a next‑generation animal model to enable basic and translational AD research. We have developed a Tg rat model (line TgF344‑AD) expressing mutant human APPsw and PS1ΔE9 genes, each independently causing early‑onset familial AD. TgF344‑AD rats manifest age‑dependent cerebral amyloidosis that precedes tauopathy, gliosis, apoptotic loss of neurons in the cerebral cortex and hippocampus, and cognitive disturbance, demonstrating progressive Alzheimer‑type neurodegeneration.

Abstract

Alzheimer's disease (AD) is hallmarked by amyloid plaques, neurofibrillary tangles, and widespread cortical neuronal loss (Selkoe, 2001). The "amyloid cascade hypothesis" posits that cerebral amyloid sets neurotoxic events into motion that precipitate Alzheimer dementia (Hardy and Allsop, 1991). Yet, faithful recapitulation of all AD features in widely used transgenic (Tg) mice engineered to overproduce Aβ peptides has been elusive. We have developed a Tg rat model (line TgF344-AD) expressing mutant human amyloid precursor protein (APPsw) and presenilin 1 (PS1ΔE9) genes, each independent causes of early-onset familial AD. TgF344-AD rats manifest age-dependent cerebral amyloidosis that precedes tauopathy, gliosis, apoptotic loss of neurons in the cerebral cortex and hippocampus, and cognitive disturbance. These results demonstrate progressive neurodegeneration of the Alzheimer type in these animals. The TgF344-AD rat fills a critical need for a next-generation animal model to enable basic and translational AD research.