Genetic Ablation of Apolipoprotein A-IV Accelerates Alzheimer's Disease Pathogenesis in a Mouse Model

Abstract

The link between lipoprotein metabolism and Alzheimer's disease (AD) has been established. Apolipoprotein A-IV (apoA-IV), a component of lipoprotein particles similar to apolipoprotein E, has been suggested to play an important role in brain metabolism. Although there are clinical debates on the function of its polymorphism in AD, the pathologic role of apoA-IV in AD is still unknown. Here, we report that genetic ablation of apoA-IV is able to accelerate AD pathogenesis in mice. In a mouse model that overexpresses human amyloid precursor protein (APP) and presenilin 1, genetic reduction of apoA-IV augments extracellular amyloid-β peptide (Aβ) burden and aggravates neuron loss in the brain. In addition, genetic ablation of apoA-IV also accelerates spatial learning deficits and increases the mortality of mice. We have found that apoA-IV colocalizes within Aβ plaques in APP/presenilin 1 transgenic mice and binds to Aβ in vitro. Subsequent studies show that apoA-IV in this model facilitates Aβ uptake in the Aβ clearance pathway mediated by astrocytes rather than the amyloidogenic pathway of APP processing. Taken together, we conclude that apoA-IV deficiency increases Aβ deposition and results in cognitive damage in the mouse model. Enhancing levels of apoA-IV may have therapeutic potential in AD treatment.

Serum Proteomic Analysis of Extracorporeal Shock Wave Therapy–Enhanced Diabetic Wound Healing in a Streptozotocin-Induced Diabetes Model

“…Serine protease inhibitor A3 is an inhibitor of several proteases, such as elastase, cathepsin G, and chymase derived from mast cells and neutrophils. 38 Apolipoprotein A-IV is a component of lipoprotein particles similar to apolipoprotein E. 39 Concentrations of inflammatory protein have been shown to be associated with apolipoprotein A-IV, which suggests a link between inflammation and apolipoprotein A-IV synthesis or catabolism. 40,41 The downregulation of apolipoprotein A-IV precursor and serine protease inhibitor A3N found in serum of extracorporeal shock wavetreated rats should support the fact that they both are important factors in enhancing wound healing after extracorporeal shock wave therapy through suppression of the inflammatory response.…”

Relation between plasma and brain lipids

“…ApoC-I colocalizes with amyloid-b plaques in human Alzheimer's disease brain [88], has been suggested to influence neuroinflammation in Alzheimer's disease [89], and may contribute to genetic susceptibility possibly via linkage disequilibrium with APOE e4 [89][90][91]. In Alzheimer's disease mice, Apoa4 deficiency increases amyloid-b load, enhances neuronal loss, accelerates cognitive dysfunction, and increases mortality [92]. Lastly, apoC-III has recently been reported to be associated with amyloid-b levels in the periphery and is of possible interest for use as an early biomarker for Alzheimer's disease [93].…”

ApoA-IV promotes the biogenesis of apoA-IV-containing HDL particles with the participation of ABCA1 and LCAT

“…ApoA-IV was also shown to bind saturably to cell surface sites ( 21,24 ), as well as to hepatic cell membranes ( 25 ), to potentiate the apoCII-mediated activation of lipoprotein lipase ( 26 ) and the activity of cholesteryl ester transfer protein ( 27 ). Furthermore, apoA-IV was reported to have anti-oxidant ( 28 ) and anti-infl ammatory ( 16,29 ) properties, and similarly to apoA-I ( 30 ), and apoE ( 31 ), may also play some role in the development of Alzheimer's disease ( 32 ). A difference between apoA-IV and apoA-I or apoE exists on the contribution of the C-terminal domain of these proteins to the solubilization of dimyristoyl-L -␣ -phosphatidyl-choline (DMPC) phospholipids ( 33,34 ).…”