Affiliations: Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
Correspondence:
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Correspondence to: Khalid Iqbal, Ph.D., Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA. Tel.: +1 718 494 5259; E-mail: khalid.iqbal.ibr@gmail.com.
Note: [1] This was the thinking of Inge Grundke-Iqbal who passed away unexpectedly on September 22, 2012 and to whom this article is dedicated.
Abstract: Alzheimer's disease is multifactorial and involves several different mechanisms. The sporadic form of the disease accounts for over 99% of the cases. As of yet, there is no practical and widely available animal model of the sporadic form of the disease. In the Alzheimer's disease brain, the lysosomal enzyme asparaginyl endopeptidase is activated and translocated from the neuronal lysosomes to the cytoplasm, probably due to brain acidosis caused by ischemic changes associated with age-associated microinfarcts. The activated asparaginyl endopeptidase cleaves inhibitor-2 of protein phosphatase-2A, I2PP2A, into I2NTF and I2CTF which translocate to the neuronal cytoplasm and inhibit the protein phosphatase activity and consequently the abnormal hyperphosphorylation of tau. Employing adeno-associated virus serotype 1 (AAV1) vector containing I2NTF-CTF and transduction of the brains of newborn rat pups with this virus, an animal model has been generated. The AAV1-I2NTF-CTF rats show neurodegeneration and cognitive impairment at 4 months and abnormal hyperphosphorylation and aggregation of tau and intraneuronal accumulation of amyloid-β at 13 months. The AAV1-I2NTF-CTF rats not only offer a disease-relevant model of the sporadic form of Alzheimer's disease but also represent a practical and widely available animal model. This short perspective on the need to focus on and develop the disease-relevant models of the sporadic form of Alzheimer's disease very much reflects the thinking of Inge Grundke-Iqbal who passed away on September 22, 2012 and to whom this article is dedicated.
Keywords: Asparaginyl endopeptidase, non-transgenic rat model of sporadic Alzheimer's disease, protein phosphatase-2A, rat model of sporadic Alzheimer's disease, tau protein, tauopathies
