Editors' ChoiceNeurodegeneration

PP2A to Alzheimer’s rescue

Sci. Signal.  29 Mar 2016:
Vol. 9, Issue 421, pp. ec71
DOI: 10.1126/scisignal.aaf7580

The serine/threonine protein phosphatase PP2A is a heterotrimeric protein composed of a scaffold subunit, catalytic subunit, and a regulatory subunit. Reduced function of PP2A has been implicated in Alzheimer’s disease. C-terminal methylation of the PP2A catalytic subunit promotes the formation of the holoenzyme, and methylated PP2A has high activity toward tau, a protein associated with Alzheimer’s disease. Leucine carboxyl methyltransferase 1 (LCMT-1) methylates PP2A and protein phosphatase methylesterase 1 (PME-1) demethylates PP2A. Nicholls et al. generated two transgenic mice, which either overexpressed FLAG-tagged PME-1 or FLAG-tagged LCMT-1 in neurons in the forebrain, including the hippocampus, which is affected in Alzheimer’s disease. Western blot analysis of hippocampal lysates from these mice showed that the PME-1–transgenic mice had reduced PP2A methylation and increased tau phosphorylation at sites targeted by PP2A. In contrast, PP2A methylation was unchanged in the LCMT-1–transgenic mice, which may be because even in wild-type mice PP2A methylation is high. Compared with control mice, both types of transgenic mice had similar amounts of the amyloid peptide Aβ, a contributor of Alzheimer’s disease pathology, and similar ability to develop long-term potentiation (LTP), a measure of synaptic plasticity that is associated with learning and memory. However, when subjected to contextual fear conditioning and water maze tasks, the PME-1–transgenic mice administered pathologic concentrations of synthetic, oligomeric β-amyloid (Aβ) exhibited poor performance compared with control mice without PME-1 overexpression or Aβ administrations. In contrast, the LCMT-1–transgenic mice administered pathological concentrations of Aβ showed better performance. Furthermore, consistent with the behavioral test responses, the LCMT-1–transgenic mice exhibited protection from Aβ-mediated impairment of LTP and the PME-1–transgenic mice exhibited enhanced sensitivity to LTP impairment by Aβ. This indicated that PME-1 increased the sensitivity of the animals and LCMT-1 reduced the sensitivity of the animals to synaptic impairment caused by pathological Aβ. Thus, this study suggested that enhancing PP2A activity reduced Aβ toxicity rather than Aβ production itself, which suggests that the toxic effects of Aβ could be therapeutically ameliorated without having to reduce Aβ production.

R. E. Nicholls, J.-M. Sontag, H. Zhang, A. Staniszewski, S. Yan, C. Y. Kim, M. Yim, C. M. Woodruff, E. Arning, B. Wasek, D. Yin, T. Bottiglieri, E. Sontag, E. R. Kandel, O. Arancio, PP2A methylation controls sensitivity and resistance to β-amyloid–induced cognitive and electrophysiological impairments. Proc. Natl. Acad. Sci. U.S.A. 113, 3347–3352 (2016). [PubMed]