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

Neurotherapeutics. 2018 Oct;15(4):1036-1054. doi: 10.1007/s13311-018-0669-5.

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.

Keywords: Alzheimer’s disease; L-arginine; L-norvaline; arginase; mTOR.; ribosomal protein S6 kinase β-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Arginase / metabolism
  • Calcium-Binding Proteins / metabolism
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / ultrastructure
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / etiology*
  • Cognition Disorders / pathology
  • Dendritic Spines / drug effects
  • Dendritic Spines / pathology
  • Dendritic Spines / ultrastructure
  • Hippocampus / drug effects
  • Hippocampus / pathology
  • Male
  • Maze Learning / drug effects
  • Mice
  • Mice, Transgenic
  • Microfilament Proteins / metabolism
  • Microglia / pathology
  • Mutation / genetics
  • Neurons / drug effects
  • Neurons / pathology
  • Presenilin-1 / genetics
  • Valine / analogs & derivatives*
  • Valine / therapeutic use
  • tau Proteins / genetics

Substances

  • Aif1 protein, mouse
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Calcium-Binding Proteins
  • Microfilament Proteins
  • PSEN1 protein, human
  • Presenilin-1
  • tau Proteins
  • norvaline
  • Arg1 protein, mouse
  • Arg2 protein, mouse
  • Arginase
  • Valine