Brain 5‐lipoxygenase over‐expression worsens memory, synaptic integrity, and tau pathology in the P301S mice

Abstract

SummaryProgressive accumulation of highly phosphorylated tau protein isoforms is the main feature of a group of neurodegenerative diseases collectively called tauopathies. Data from human and animal models of these diseases have shown that neuroinflammation often accompanies their pathogenesis. The 5‐lipoxygenase (5LO) is an enzyme widely expressed in the brain and a source of potent pro‐inflammatory mediators, while its pharmacological inhibition modulates the phenotype of a tau transgenic mouse model, the htau mice. By employing an adeno‐associated viral vector system to over‐express 5LO in the brain, we examined its contribution to the behavioral deficits and neuropathology in a different transgenic mouse model of tauopathy, the P301S mouse line. Compared with controls, 5LO‐targeted gene brain over‐expression in these mice resulted in a worsening of behavioral and motor deficits. Over‐expression of 5LO resulted in microglia and astrocyte activation and significant synaptic pathology, which was associated with a significant elevation of tau phosphorylation at specific epitopes, tau insoluble fraction, and activation of the cdk5 kinase. In vitro studies confirmed that 5LO directly modulates tau phosphorylation at the same epitopes via the cdk5 kinase pathway. These data demonstrate that 5LO plays a direct role in tau phosphorylation and is an active player in the development of the entire tau phenotype. They provide further support to the hypothesis that 5LO is a viable therapeutic target for the treatment and/or prevention of human tauopathy.

The Chemical Biology of Ferroptosis in the Central Nervous System

“…In this model, in vitro and in vivo studies suggest that it is 5-lipoxygenase localized at the nuclear envelope that executes ferroptosis (Karuppagounder et al, 2018). Therefore, the development of brain-penetrant inhibitors of 5-lipoxygenase that are active in mice and humans could be an effective strategy for treating parenchymal brain hemorrhage or Alzheimer's disease (Vagnozzi et al, 2018).…”

Intersection of pathological tau and microglia at the synapse

“…In addition to the effects of cytokines on kinases and phosphates, it was recently shown that metalloproteinase MMP-9 causes tau aggregation via deacetylase HDAC6 [299]. Furthermore, the leukotrine 5-Lipoxygenase is upregulated in tauopathies, worsens tau pathology, neuroinflammation, and increases synapse loss [58, 108–111, 184, 300, 301]. More studies are needed to identify if and how microglia can initiate tau aggregation, rather than mere aggravation of existing tau pathology.…”

Tau inhibits PKA by nuclear proteasome‐dependent PKAR2α elevation with suppressed CREB/GluA1 phosphorylation

“…CREB is one of the pivotal transcription factors regulating the expression of various synaptic proteins. Studies show that extracellular application of tau oligomers or direct overexpression of tau or hyperphosphorylation and accumulation of tau by various molecules all reduced synaptic protein expression and disrupted glutamate receptor trafficking (Hoover et al, ; Puzzo et al, ; Vagnozzi, Giannopoulos, & Pratico, ). By overexpression hTau in primary hippocampal neurons, the decreased protein levels of BDNF, GluN1, GluN2A, GluA1, GluA2, PSD93, PSD95, and SYT were also detected with unchanged GluN2B, SYP, and SYN1.…”