Vitamin D-binding protein interacts with Aβ and suppresses Aβ-mediated pathology

The level of vitamin D-binding protein (DBP) is increased in the cerebrospinal fluid of patients with Alzheimer''s disease (AD), suggesting a relationship with its pathogenesis. In this study, we investigated whether and how DBP is related to AD using several different approaches. A pull-down assay and a surface plasmon resonance binding assay indicated direct interactions between purified DBP and amyloid beta (Aβ), which was confirmed in the brain of AD patients and transgenic AD model mice by immunoprecipitation assay and immunohistochemical double-staining method. Moreover, atomic force microscopic examination revealed that DBP reduced Aβ aggregation in vitro. DBP also prevented Aβ-mediated death in cultured mouse hippocampal HT22 cell line. Finally, DBP decreased Aβ-induced synaptic loss in the hippocampus and rescued memory deficits in mice after injection of Aβ into the lateral ventricle. These results provide converging evidence that DBP attenuates the harmful effects of Aβ by a direct interaction, and suggest that DBP is a promising therapeutic agent for the treatment of AD.     

RNA oxidation: A contributing factor or an epiphenomenon in the process of neurodegeneration

In the past decade, RNA oxidation has caught the attention of many researchers, working to uncover its role in the pathogenesis of neurodegenerative diseases. It has been well documented that RNA oxidation is involved in a wide variety of neurological diseases and is an early event in the process of neurodegeneration. The analysis of oxidized RNA species revealed that at least messenger RNA (mRNA) and ribosomal RNA (rRNA) are damaged in several neurodegenerative diseases, including Alzheimer's disease and amyotrophic lateral sclerosis (ALS). The magnitude of the RNA oxidation, at least in mRNA, is significantly high at the early stage of the disease. Oxidative damage to mRNA is not random but selective and many oxidized mRNAs are related to the pathogenesis of the disease. Several studies have suggested that oxidative modification of RNA affects the translational process and consequently produces less protein and/or defective protein. Furthermore, several proteins have been identified to be involved in handling of damaged RNA. Although a growing body of studies suggests that oxidative damage to RNA may be associated with neuron deterioration, further investigation and solid evidence are needed. In addition, further uncovering of the consequences and cellular handling of the oxidatively damaged RNA should be important focuses in this area and may provide significant insights into the pathogenesis of neurodegenerative diseases.     

Young microglia restore amyloid plaque clearance of aged microglia

Alzheimer′s disease (AD) is characterized by deposition of amyloid plaques, neurofibrillary tangles, and neuroinflammation. In order to study microglial contribution to amyloid plaque phagocytosis, we developed a novel ex vivo model by co‐culturing organotypic brain slices from up to 20‐month‐old, amyloid‐bearing AD mouse model (APPPS1) and young, neonatal wild‐type (WT) mice. Surprisingly, co‐culturing resulted in proliferation, recruitment, and clustering of old microglial cells around amyloid plaques and clearance of the plaque halo. Depletion of either old or young microglial cells prevented amyloid plaque clearance, indicating a synergistic effect of both populations. Exposing old microglial cells to conditioned media of young microglia or addition of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) was sufficient to induce microglial proliferation and reduce amyloid plaque size. Our data suggest that microglial dysfunction in AD may be reversible and their phagocytic ability can be modulated to limit amyloid accumulation. This novel ex vivo model provides a valuable system for identification, screening, and testing of compounds aimed to therapeutically reinforce microglial phagocytosis.     

Protein interaction network for Alzheimer's disease using computational approach

Alzheimer''s disease (AD) is the most common form of dementia. It is the sixth leading cause of death in old age people. Despiterecent advances in the field of drug design, the medical treatment for the disease is purely symptomatic and hardly effective. Thusthere is a need to understand the molecular mechanism behind the disease in order to improve the drug aspects of the disease. Weprovided two contributions in the field of proteomics in drug design. First, we have constructed a protein-protein interactionnetwork for Alzheimer''s disease reviewed proteins with 1412 interactions predicted among 969 proteins. Second, the diseaseproteins were given confidence scores to prioritize and then analyzed for their homology nature with respect to paralogs andhomologs. The homology persisted with the mouse giving a basis for drug design phase. The method will create a new drug designtechnique in the field of bioinformatics by linking drug design process with protein-protein interactions via signal pathways. Thismethod can be improvised for other diseases in future.     

TGF-β1 is an organizer of responses to neurodgeneration

TGF-β1 mRNA and protein were recently found to increase in animal brains after experimental lesions that cause local deafferentation or neuron death. Elevations of TGF-β1 mRNA after lesions are prominent in microglia but are also observed in neurons and astrocytes. Moreover, TGF-β1 mRNA autoinduces its own mRNA in the brain. These responses provide models for studying the increases of TGF-β1 protein observed in βA/amyloid-containing extracellular plaques of Alzheimer's disease (AD) and Down's syndrome (DS) and in brain cells of AIDS victims. Involvement of TGF-β1 in these human brain disorders is discussed in relation to the potent effects of TGF-β1 on wound healing and inflammatory responses in peripheral tissues. We hypothesize that TGF-β1 and possibly other TGF-β peptides have organizing roles in responses to neurodegeneration and brain injury that are similar to those observed in non-neural tissues. Work from many laboratories has shown that activities of TGF-β peptides on brain cells include chemotaxis, modification of extracellular matrix, and regulation of cytoskeletal gene expression and of neurotrophins. Similar activities of the TGF-β's are well established in other tissues.     

Distinct prion-like strains of amyloid beta implicated in phenotypic diversity of Alzheimer's disease

Vast evidence on human prions demonstrates that variable disease phenotypes, rates of propagation, and targeting of distinct brain structures are determined by unique conformers (strains) of pathogenic prion protein (PrP^Sc). Recent progress in the development of advanced biophysical tools that inventory structural characteristics of amyloid beta (Aβ) in the brain cortex of phenotypically diverse Alzheimer's disease (AD) patients, revealed unique spectrum of oligomeric particles in the cortex of rapidly progressive cases, implicating these structures in variable rates of propagation in the brain, and in distict disease manifestation. Since only ～30% of phenotypic diversity of AD can be explained by polymorphisms in risk genes, these and transgenic bioassay data argue that structurally distinct Aβ particles play a major role in the diverse pathogenesis of AD, and may behave as distinct prion-like strains encoding diverse phenotypes. From these observations and our growing understanding of prions, there is a critical need for new strain-specific diagnostic strategies for misfolded proteins causing these elusive disorders. Since targeted drug therapy can induce mutation and evolution of prions into new strains, effective treatments of AD will require drugs that enhance clearance of pathogenic conformers, reduce the precursor protein, or inhibit the conversion of precursors into prion-like states.