Neurotoxicity Of Amyloid Β-protein Research Articles

ApoE and Aβ in Alzheimer’s Disease: Accidental Encounters or Partners?

Among the three human apolipoprotein E (apoE) isoforms, apoE4 increases the risk of Alzheimer's disease (AD). While transporting cholesterol is a primary function, apoE also regulates amyloid-β (Aβ) metabolism, aggregation, and deposition. Although earlier work suggests that different affinities of apoE isoforms to Aβ might account for their effects on Aβ clearance, recent studies indicate that apoE also competes with Aβ for cellular uptake through apoE receptors. Thus, several factors probably determine the variable effects apoE has on Aβ. In this Review, we examine biochemical, structural, and functional studies and propose testable models that address the complex mechanisms underlying apoE-Aβ interaction and how apoE4 may increase AD risk and also serve as a target pathway for therapy.

In vitro and in vivo comparisons of the effects of the fruiting body and mycelium of Antrodia camphorata against amyloid β-protein-induced neurotoxicity and memory impairment

Antrodia camphorata is a particular and precious medicinal mushroom, and its fruiting body was found to provide more efficient protection from oxidative stress and inflammation than its mycelium because of its higher content of triterpenoids, total phenols, and so on. In the previous in vitro studies, the mycelium of A. camphorata is proven to provide strong neuroprotection in neuron cells and suggested to have the potential of protection against neurotoxicity of amyloid β-protein (Aβ) known as the risk factor toward Alzheimer's disease (AD) development. However, the in vivo study and the comparison study with the fruiting body have not yet been investigated. This study compared the effect of the fruiting body and mycelium of A. camphorata on alleviating the Aβ40-induced neurocytotoxicity in the in vitro Aβ-damaged neuron cell model (PC-12 cell treated with Aβ40) and memory impairment in the in vivo AD animal model induced with a continuous brain infusion of Aβ40. In the results of in vitro and in vivo studies, the fruiting body possessed stronger anti-oxidative and anti-inflammatory abilities for inhibiting neurocytotoxicity in Aβ40-treated PC-12 cells and Aβ40 accumulation in Aβ40-infused brain than mycelium. Moreover, hyperphosphorylated tau (p-tau) protein expression, known as an important AD risk factor, was suppressed by the treatment of fruiting body rather than that of mycelium in the in vitro and in vivo studies. These comparisons supported the reasons why the fruiting body resulted in a more significant improvement effect on working memory ability than mycelium in the AD rats.

Perineuronal nets protect against amyloid β-protein neurotoxicity in cultured cortical neurons

Perineuronal nets (PNs) consisting of chondroitin sulfate proteoglycans (CSPGs) and hyaluronic acid are associated with distinct neuronal populations in mammalian brain. Cortical areas abundant in PNs have been known to be less affected by neurotoxicity in human Alzheimer's disease. In the present study, we examined whether PNs protect the neurotoxicity caused by amyloid β-protein (Aβ), a major constituent of senile plaques in Alzheimer's disease using cortical neurons of dissociated culture. Double labeling experiments using confocal microscopy showed that the neurons associated with PNs were visualized with the anti-CSPG antibody in dissociated cortical culture. The analysis of reverse transcription-polymerase chain reaction revealed that mRNA expression of chondroitin sulfotransferases, CSPG-specific enzymes, was detected in neuronal culture, indicating that cultured cortical neurons are able to synthesize CSPGs and construct PNs structure. The treatment of Aβ1–42 showed significant neurotoxicity on PNs-free cortical neurons, however, it did not reveal neurotoxicity on PNs-associated neurons. Moreover, it was shown that the treatment of Aβ1–42 was able to kill PNs-associated neurons after the removal of chondroitin sulfate (CS) glycosaminoglycans with chondroitinase ABC. The treatment of glutamate killed not only PNs-free cortical neurons but also PNs-associated neurons. These results suggest that CS glycosaminoglycans on PNs are responsible for protecting neurons from Aβ1–42 neurotoxicity.

Study of the interaction of Zn 2+ with Aβ(10-21) by fluorescamine assay

Zinc may play a role as a co-factor in the pathogenesis of Alzheimer's disease (AD) through influencing the conformation and neurotoxicity of amyloid β-protein (Aβ). Using the fluorescamine assay, we show for the first time that Zn 2+ induced Aβ(10-21) aggregate in a concentration-dependent manner. These results indicate that Aβ(10-21) can be used as an in vitro model in Zn 2+-induced Aβ aggregation and that the region 10-21 to be the minimal fragment of zinc-binding domain of full length Aβ(1-42).

Aggregation and neurotoxicity of amyloid β-protein: acceleration by aluminum : Masahiro Kawahara, Kazuyo Muramoto, Kazuo Kobayashi, Hiroshi Mori ∗, Yoichiro Kuroda, Department of Molecular & Cellular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, Fuchu-shi, Tokyo 183, ∗Department of Molecular Biology, Tokyo Institute for Psychiatry, Setagaya-ku, Tokyo 156, Japan

We assessed the fibrillogenic properties of synthetic peptides corresponding to residues 13–26 of β/A4 amyloid, containing either the normal sequence (β13–26) or the mutations Glu22 to Gln (β13–26Q22) and Ala21 to Gly (β13–26G21). The kinetics of aggregation were monitored at 37°C and pH 7.4 by measuring the amount of peptide remaining in solution, using reverse-phase high performance liquid chromatography. Negative stain electron microscopy revealed that all of the peptides formed fibrils. However, β13–26Q22 showed greatly accelerated fibril formation compared to the other two. The results suggest that the Q22 mutation confers increased amyloidogenic properties on the β/A4 peptide, whereas the G21 mutation acts by a different pathogenic mechanism.