Inhibition of Protein Phosphatase-2A (PP2A) by I₁^PP2A Leads to Hyperphosphorylation of Tau, Neurodegeneration, and Cognitive Impairment in Rats

Article type: Research Article

Authors: Wang, Xiaochuan^{; 1} | Blanchard, Julie^{; 1} | Tung, Yunn Chyn | Grundke-Iqbal, Inge^{; 2} | Iqbal, Khalid^{; *}

Affiliations: Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA

Correspondence: [*] Correspondence to: Khalid Iqbal, PhD, Department of Neurochemistry, 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: [email protected].

Note: [1] These authors contributed equally to this work.

Note: [2] This paper is dedicated to Inge Grundke-Iqbal who co-supervised this study and who passed away on September 22, 2012.

Abstract: Protein phosphatase-2A (PP2A) deficiency is a cause of the abnormal hyperphosphorylation of tau, which composes neurofibrillary tangles (NFTs) in Alzheimer's disease (AD) brain. We previously reported that both mRNA and protein expression of inhibitor I of PP2A (I1PP2A) are elevated in AD brain and that this inhibitor induces a dose-dependent inhibition of PP2A activity and tau hyperphosphorylation in NIH3T3 cells. However, whether I1PP2A can induce AD neurofibrillary degeneration and cognitive impairment was not known. In the present study, we infected the brains of rat pups within 24 hours of birth with adeno-associated virus serotype 1 (AAV1) carrying I1PP2A. In the adult AAV1-I1PP2A rats, we found a decrease in PP2A activity and abnormal hyperphosphorylation of tau in the brain. Immunohistochemistry showed a significant reduction of MAP2 and synapsin 1 in AAV1- I1PP2A animals, suggesting that I1PP2A can induce a loss of dendritic and synaptic plasticity markers. Behavioral tests revealed that infection with AAV1- I1PP2A induced deficits in exploratory activity, spatial reference memory, and memory consolidation in adult rats. These studies suggest that I1PP2A can inhibit PP2A activity, and in turn induce AD neurofibrillary degeneration and cognitive deficits in rats.

Keywords: Inhibitor I of PP2A (I₁^PP2A), neurofibrillary degeneration, protein phosphatase-2A (PP2A), tau hyperphosphorylation

DOI: 10.3233/JAD-142403

Journal: Journal of Alzheimer's Disease, vol. 45, no. 2, pp. 423-435, 2015