title: Alzheimer disease and amyotrophic lateral sclerosis: an etiopathogenic connection.
abstract: The etiopathogenesis of neither the sporadic form of Alzheimer disease (AD) nor of amyotrophic lateral sclerosis (ALS) is well understood. The activity of protein phosphatase-2A (PP2A), which regulates the phosphorylation of tau and neurofilaments, is negatively regulated by the myeloid leukemia-associated protein SET, also known as inhibitor-2 of PP2A, I2(PP2A). In AD brain, PP2A activity is compromised, probably because I2(PP2A) is overexpressed and is selectively cleaved at asparagine 175 into an N-terminal fragment, I2NTF, and a C-terminal fragment, I2CTF, and both fragments inhibit PP2A. Here, we analyzed the spinal cords from ALS and control cases for I2(PP2A) cleavage and PP2A activity. As observed in AD brain, we found a selective increase in the cleavage of I2(PP2A) into I2NTF and I2CTF and inhibition of the activity and not the expression of PP2A in the spinal cords of ALS cases. To test the hypothesis that both AD and ALS could be triggered by I2CTF, a cleavage product of I2(PP2A), we transduced by intracerebroventricular injections newborn rats with adeno-associated virus serotype 1 (AAV1) containing human I2CTF. AAV1-I2CTF produced reference memory impairment and tau pathology, and intraneuronal accumulation of Aβ by 5-8 months, and motor deficit and hyperphosphorylation and proliferation of neurofilaments, tau and TDP-43 pathologies, degeneration and loss of motor neurons and axons in the spinal cord by 10-14 months in rats. These findings suggest a previously undiscovered etiopathogenic relationship between sporadic forms of AD and ALS that is linked to I2(PP2A) and the potential of I2(PP2A)-based therapeutics for these diseases.
authors.affiliation: 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, 10314-6399, USA.
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Wang
authors.forename: Julie
authors.initials: J
authors.lastname: Blanchard
authors.forename: Inge
authors.initials: I
authors.lastname: Grundke-Iqbal
authors.forename: Jerzy
authors.initials: J
authors.lastname: Wegiel
authors.forename: Han-Xiang
authors.initials: HX
authors.lastname: Deng
authors.forename: Teepu
authors.initials: T
authors.lastname: Siddique
authors.forename: Khalid
authors.initials: K
authors.lastname: Iqbal
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D004268:DNA-Binding Proteins; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D056488:Histone Chaperones / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D014161:Transduction, Genetic; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; C513473:SET protein, human; D014157:Transcription Factors; D016875:tau Proteins; D054648:Protein Phosphatase 2