Potential Neuroprotective Effects of Adiponectin in Alzheimer's Disease

Abstract

The adipocyte-secreted protein adiponectin (APN) has several protective functions in the peripheral tissues including insulin sensitizing, anti-inflammatory and anti-oxidative effects that may benefit neurodegenerative diseases such as Alzheimer's disease (AD). In addition, dysregulation of cerebral insulin sensitivities and signaling activities have been implicated in AD. Emerging insights into the mechanistic roles of adiponectin and AD highlight the potential therapeutic effects for AD through insulin signaling.

Keywords: Alzheimer’s disease; Amyloid-β; adiponectin; cognitive impairments.

Figure 1

Pathophysiological roles of adiponectin in Alzheimer’s disease (AD). Schematic outline of neuronal adiponectin signaling in the normal brain (A); and adiponectin-deficient brain (B). Under physiological conditions, adiponectin binds to its receptor and triggers phosphorylation of AMPK which inhibits IRS-1 phosphorylation at serine residues. This increases insulin-mediated IRS-1 phosphorylation at tyrosine residues and promotes downstream Akt-mediated GSK3 inhibition. Inhibition of GSK3 slows down phosphorylation of Tau and APP metabolism. In AD, chronic adiponectin deficiency leads to an increase of IRS-1 phosphorylation at serine residues (e.g., Serine 616). This causes reduced pIRS-1Tyr and results in GSK3 activation. Activated GSK3 enhances Tau phosphorylation and Aβ production in neurons. Arrows denote promotion, T-bars denote inhibition.

Figure 2

Strategies to increase adiponectin signaling in AD neurons. Peripherally, adiponectin expression from the liver, adipocytes and muscle can be increased by administering PPARγ agonist (e.g., pioglitazone) and physical exercise induction. Physical exercise can also increase the transport of low molecular weight nd trimeric adiponectin across the blood-brain barrier (BBB). Administration of adipoR agonists and LMW adiponectin acts on AdipoR1 in neurons and microglia to exert neuroprotection. Green arrow denotes increase, arrows and dash arrows denote promotion, T-bars denote inhibition.