A novel etiopathogenic mechanism and a disease-relevant non-transgenic rat model of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is pathologically characterized by the presence of numerous intracellular neurofibrillary tangles and extracellular β-amyloid plaques. Development of rational therapeutical treatments of AD requires the elucidation of the mechanisms that lead to tau protein pathology and β-amyloidosis. We employed an adeno-associated virus serotype 1 (AAV1)-induced expression of the C-terminal fragment (I2CTF) of I2PP2A/SET and infected newborn Wistar rat pups by bilateral intracerebroventricular (ICV) injection with the AAV1- I2CTF. I2CTF, tau phosphorylation and neurodegeneration were studied immunohistochemically and by Western blot. The reference memory of the animals was evaluated by a spatial reference memory task in the water maze. The AAV1- I2CTF induced a decrease in brain protein phosphatase 2A (PP2A) activity, abnormal hyperphosphorylation of tau and neurodegeneration. Furthermore, there was an increase in the level of activated glycogen synthase kinase-3β and enhanced expression of intraneuronal Aβ in AAV1-I2CTF animals. Morris Water Maze behavioral test revealed that infection with AAV1-I2CTF induced a spatial reference memory and memory consolidation deficit. Finally, this cognitive impairment was associated with a decrease in the brain level of pSer133-CREB. This findings of this study suggest (1) a novel etiopathogenic mechanism of AD which is initiated by the cleavage of I2PP2A, producing I2CTF and (2) provide a practical, non-transgenic animal model which is based on an etiopathogenic mechanism of AD.