Amyloid β (Aβ) plays a pivotal role in the progression of Alzheimer's disease (AD) through its neurotoxic and inflammatory effects. On one hand, Aβ binds to microglia and activates them to produce inflammatory mediators. On the other hand, Aβ is cleared by microglia through receptor-mediated phagocytosis and degradation. This review focuses on microglial membrane receptors that bind Aβ and contribute to microglial activation and/or Aβ phagocytosis and clearance. These receptors can be categorized into several groups. The scavenger receptors (SRs) include scavenger receptor A-1 (SCARA-1), MARCO, scavenger receptor B-1 (SCARB-1), CD36 and the receptor for advanced glycation end product (RAGE). The G protein-coupled receptors (GPCRs) are formyl peptide receptor 2 (FPR2) and chemokine-like receptor 1 (CMKLR1). There are also toll-like receptors (TLRs) including TLR2, TLR4, and the co-receptor CD14. Functionally, SCARA-1 and CMKLR1 are involved in the uptake of Aβ, and RAGE is responsible for the activation of microglia and production of proinflammatory mediators following Aβ binding. CD36, CD36/CD47/α6β1-intergrin, CD14/TLR2/TLR4, and FPR2 display both functions. Additionally, MARCO and SCARB-1 also exhibit the ability to bind Aβ and may be involved in the progression of AD. Here, we focus on the expression and distribution of these receptors in microglia and their roles in microglia interaction with Aβ. Finally, we discuss the potential therapeutic value of these receptors in AD.

Tau is a neuronal microtubule‐associated protein. Its hyperphosphorylation plays a critical role in Alzheimer disease (AD). Expression and phosphorylation of tau are regulated developmentally, but its dynamic regulation and the responsible kinases or phosphatases remain elusive. Here, we studied the developmental regulation of tau in rats during development from embryonic day 15 through the age of 24 months. We found that tau expression increased sharply during the embryonic stage and then became relatively stable, whereas tau phosphorylation was much higher in developing brain than in mature brain. However, the extent of tau phosphorylation at seven of the 14 sites studied was much less in developing brain than in AD brain. Tau phosphorylation during development matched the period of active neurite outgrowth in general. Tau phosphorylation at various sites had different topographic distributions. Several tau kinases appeared to regulate tau phosphorylation collectively at overlapping sites, and the decrease of overall tau phosphorylation in adult brain might be due to the higher levels of tau phosphatases in mature brain. These studies provide new insight into the developmental regulation of site‐specific tau phosphorylation and identify the likely sites required for the abnormal hyperphosphorylation of tau in AD.

O-GlcNAcylation is a common posttranslational modification of nucleocytoplasmic proteins by β-N-acetylglucosamine (GlcNAc). The dynamic addition and removal of O-GlcNAc groups to and from proteins are catalyzed by O-linked N-acetylglucosamine transferase (O-GlcNAc transferase, OGT) and β-N-acetylglucosaminidase (O-GlcNAcase, OGA), respectively. O-GlcNAcylation often modulates protein phosphorylation and regulates several cellular signaling and functions, especially in the brain. However, its developmental regulation is not well known. Here, we studied protein O-GlcNAcylation, OGT, and OGA in the rat brain at various ages from embryonic day 15 to the age of 2 years. We found a gradual decline of global protein O-GlcNAcylation during developmental stages and adulthood. This decline correlated positively to the total protein phosphorylation at serine residues, but not at threonine residues. The expression of OGT and OGA isoforms was regulated differently at various ages. Immunohistochemical studies revealed ubiquitous distribution of O-GlcNAcylation at all ages. Strong immunostaining of O-GlcNAc, OGT, and OGA was observed mostly in neuronal cell bodies and processes, further suggesting the role of O-GlcNAc modification of neuronal proteins in the brain. These studies provide fundamental knowledge of age-dependent protein modification by O-GlcNAc and will help guide future studies on the role of O-GlcNAcylation in the mammalian brain.

Vascular recovery or re-angiogenesis after radiotherapy plays a significant role in tumor recurrence, whereas molecular mechanisms of this process remain elusive. In this work, we found that dying glioma cells promoted post-irradiation angiogenesis through a caspase 3 dependent mechanism. Evidence in vitro and in vivo indicated that caspase 3 inhibition undermined proangiogenic effects of dying glioma cells. Proteolytic inactivation of caspase 3 in glioma cells reduced tumorigenicity. Importantly, we identified that NF-κB/COX-2/PGE2 axis acted as downstream signaling of caspase 3, mediating proangiogenic response after irradiation. Additionally, VEGF-A, regulated by caspase 3 possibly through phosphorylated eIF4E, was recognized as another downstream factor participating in the proangiogenic response. In conclusion, these data demonstrated that caspase 3 in dying glioma cells supported the proangiogenic response after irradiation by governing NF-κB/COX-2/PGE2 axis and p-eIF4E/VEGF-A signaling. While inducing caspase 3 activation has been a generally-adopted notion in cancer therapeutics, our study counterintuitively illustrated that caspase 3 activation in dying glioma cells unfavorably supported post-irradiation angiogenesis, suggesting that radiotherapy combined with caspase 3 inhibitors may be more effective strategies due to restricted post-irradiation angiogenesis.