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An experimental rat model of sporadic Alzheimer’s disease and rescue of cognitive impairment with a neurotrophic peptide

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Abstract

Alzheimer’s disease (AD) is multifactorial and, to date, no single cause of the sporadic form of this disease, which accounts for over 99% of the cases, has been established. In AD brain, protein phosphatase-2A (PP2A) activity is known to be compromised due to the cleavage and translocation of its potent endogenous inhibitor, I 2 PP2A , from the neuronal nucleus to the cytoplasm. Here, we show that adeno-associated virus vector-induced expression of the N-terminal I2NTF and C-terminal I2CTF halves of I 2 PP2A , also called SET, in brain reproduced key features of AD in Wistar rats. The I2NTF–CTF rats showed a decrease in brain PP2A activity, abnormal hyperphosphorylation and aggregation of tau, a loss of neuronal plasticity and impairment in spatial reference and working memories. To test whether early pharmacologic intervention with a neurotrophic molecule could rescue neurodegeneration and behavioral deficits, 2.5-month-old I2NTF–CTF rats and control littermates were treated for 40 days with Peptide 6, an 11-mer peptide corresponding to an active region of the ciliary neurotrophic factor. Peripheral administration of Peptide 6 rescued neurodegeneration and cognitive deficit in I2NTF–CTF animals by increasing dentate gyrus neurogenesis and mRNA level of brain derived neurotrophic factor. Moreover, Peptide 6-treated I2NTF–CTF rats showed a significant increase in dendritic and synaptic density as reflected by increased expression of synapsin I, synaptophysin and MAP2, especially in the pyramidal neurons of CA1 and CA3 of the hippocampus.

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Acknowledgments

We are most grateful to Dr. Aurelian Radu for his help in the design of the AAV1-I2NTF–CTF constructs, Dr. George Merz for his help in confocal microscopy, Drs. Ezzat El-Akkad and Jianhua Shi for their help in the preparation of the figures, and Ms. Janet Murphy for secretarial assistance. Studies described in this paper were supported in part by the New York State Office of People with Developmental Disabilities, NIH/NIA grant AG019158, and a research grant from EVER NeuroPharma, Unterach, Austria.

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Correspondence to Khalid Iqbal.

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Bolognin, S., Blanchard, J., Wang, X. et al. An experimental rat model of sporadic Alzheimer’s disease and rescue of cognitive impairment with a neurotrophic peptide. Acta Neuropathol 123, 133–151 (2012) doi:10.1007/s00401-011-0908-x

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Keywords

  • Brain Derive Neurotrophic Factor
  • Probe Trial
  • Neuronal Plasticity
  • Escape Platform
  • PP2A Activity