L-Norvaline Reverses Cognitive Decline and Synaptic Loss in a Murine Model of Alzheimer’s Disease

Baruh Polis, Kolluru D. Srikanth, Evan Elliott, Hava Gil-Henn, Abraham O. Samson

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

The urea cycle is strongly implicated in the pathogenesis of Alzheimer’s disease (AD). Arginase-I (ARGI) accumulation at sites of amyloid-beta (Aβ) deposition is associated with L-arginine deprivation and neurodegeneration. An interaction between the arginase II (ARGII) and mTOR-ribosomal protein S6 kinase β-1 (S6K1) pathways promotes inflammation and oxidative stress. In this study, we treated triple-transgenic (3×Tg) mice exhibiting increased S6K1 activity and wild-type (WT) mice with L-norvaline, which inhibits both arginase and S6K1. The acquisition of spatial memory was significantly improved in the treated 3×Tg mice, and the improvement was associated with a substantial reduction in microgliosis. In these mice, increases in the density of dendritic spines and expression levels of neuroplasticity-related proteins were followed by a decline in the levels of Aβ toxic oligomeric and fibrillar species in the hippocampus. The findings point to an association of local Aβ-driven and immune-mediated responses with altered L-arginine metabolism, and they suggest that arginase and S6K1 inhibition by L-norvaline may delay the progression of AD.

Original languageEnglish
Pages (from-to)1036-1054
Number of pages19
JournalNeurotherapeutics
Volume15
Issue number4
DOIs
StatePublished - 14 Oct 2018

Bibliographical note

Publisher Copyright:
© 2018, The Author(s).

Keywords

  • Alzheimer’s disease
  • L-arginine
  • L-norvaline
  • arginase
  • mTOR
  • ribosomal protein S6 kinase β-1

Fingerprint

Dive into the research topics of 'L-Norvaline Reverses Cognitive Decline and Synaptic Loss in a Murine Model of Alzheimer’s Disease'. Together they form a unique fingerprint.

Cite this