Alzheimer disease and amyotrophic lateral sclerosis: an etiopathogenic connection

作者：Wang Xiaochuan; Blanchard Julie; Grundke Iqbal Inge; Wegiel Jerzy; Deng Han Xiang; Siddique Teepu; Iqbal Khalid^*

来源：Acta Neuropathologica, 2014, 127(2): 243-256.

DOI：10.1007/s00401-013-1175-9

• Alzheimer's disease
• Amyotrophic lateral sclerosis
• Guam Parkinsonism dementia complex
• Protein phosphatase-2A
• Inhibitor-2 of protein phosphatase-2A
• I-2(PP2A/SET)
• Abnormal hyperphosphorylation of tau

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, I (2) (PP2A) . In AD brain, PP2A activity is compromised, probably because I (2) (PP2A) is overexpressed and is selectively cleaved at asparagine 175 into an N-terminal fragment, I-2NTF, and a C-terminal fragment, I-2CTF, and both fragments inhibit PP2A. Here, we analyzed the spinal cords from ALS and control cases for I (2) (PP2A) cleavage and PP2A activity. As observed in AD brain, we found a selective increase in the cleavage of I (2) (PP2A) into I-2NTF and I-2CTF 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 I-2CTF, a cleavage product of I (2) (PP2A) , we transduced by intracerebroventricular injections newborn rats with adeno-associated virus serotype 1 (AAV1) containing human I-2CTF. AAV1-I-2CTF produced reference memory impairment and tau pathology, and intraneuronal accumulation of A beta 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 I (2) (PP2A) and the potential of I (2) (PP2A) -based therapeutics for these diseases.

• 出版日期2014-2
• 单位西北大学