Animal models of the sporadic form of Alzheimer's disease: focus on the disease and not just the lesions.
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, I2(PP2A), into I(2NTF) and I(2CTF) 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 I(2NTF-CTF) and transduction of the brains of newborn rat pups with this virus, an animal model has been generated. The AAV1-I(2NTF-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-I(2NTF-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.
Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA.
Khalid
K
Iqbal
Silvia
S
Bolognin
Xiaochuan
X
Wang
Gustavo
G
Basurto-Islas
Julie
J
Blanchard
Yunn Chyn
YC
Tung
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D006801:Humans; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051381:Rats; D016875:tau Proteins / Q000378:metabolism
D016875:tau Proteins; D054648:Protein Phosphatase 2