MicroRNAs (miRNAs) are small regulatory RNAs that participate in posttranscriptional gene regulation in a sequence-specific manner. However, little is understood about the role(s) of miRNAs in Alzheimer's disease (AD). We used miRNA expression microarrays on RNA extracted from human brain tissue from the University of Kentucky Alzheimer's Disease Center Brain Bank with near-optimal clinicopathological correlation. Cases were separated into four groups: elderly nondemented with negligible AD-type pathology, nondemented with incipient AD pathology, mild cognitive impairment (MCI) with moderate AD pathology, and AD. Among the AD-related miRNA expression changes, miR-107 was exceptional because miR-107 levels decreased significantly even in patients with the earliest stages of pathology. In situ hybridization with cross-comparison to neuropathology demonstrated that particular cerebral cortical laminas involved by AD pathology exhibit diminished neuronal miR-107 expression. Computational analysis predicted that the 3Ј-untranslated region (UTR) of ␤-site amyloid precursor protein-cleaving enzyme 1 (BACE1) mRNA is targeted multiply by miR-107. From the same RNA material analyzed on miRNA microarrays, mRNA expression profiling was performed using Affymetrix Exon Array microarrays on nondemented, MCI, and AD patients. BACE1 mRNA levels tended to increase as miR-107 levels decreased in the progression of AD. Cell culture reporter assays performed with a subset of the predicted miR-107 binding sites indicate the presence of at least one physiological miR-107 miRNA recognition sequence in the 3Ј-UTR of BACE1 mRNA. Together, the coordinated application of miRNA profiling, Affymetrix microarrays, new bioinformatics predictions, in situ hybridization, and biochemical validation indicate that miR-107 may be involved in accelerated disease progression through regulation of BACE1.

Aging-related neurodegenerative diseases (NDs) are the culmination of many different genetic and environmental influences. Prior studies have shown that RNAs are pathologically altered during the inexorable course of some NDs. Recent evidence suggests that microRNAs (miRNAs) may be a contributing factor in neurodegeneration. miRNAs are brain-enriched, small (~22 nucleotides) non-coding RNAs that participate in mRNA translational regulation. Although discovered in the framework of worm development, miRNAs are now appreciated to play a dynamic role in many mammalian brain-related biochemical pathways, including neuroplasticity and stress responses. Research about miRNAs in the context of neurodegeneration is accumulating rapidly, and the goal of this review is to provide perspective for these new data that may be helpful to specialists in either field. An overview is provided about the normal functions for miRNAs, including some of the newer concepts related to the human brain. Recently published studies pertaining to the roles of miRNAs in NDs--including Alzheimer's disease, Parkinson's disease and triplet repeat disorders-are described. Finally, a discussion is included with theoretical syntheses and possible future directions in exploring the nexus between miRNA and ND research.

Angiogenesis is one of the most important features of AIDS-associated Kaposi's sarcoma (AIDS-KS). Our studies suggested that spindle-shaped AIDS-KS cells from various AIDS-KS lesions play important roles in the development of KS lesions. Basic fibroblast growth factor (bFGF) has been reported to be a predominant angiogenic factor expressed in AIDS-KS cells. However, our data from ELISA revealed the presence of the vascular endothelial growth factor (VEGF) molecule in large quantities in AIDS-KS cell-derived conditioned medium (AIDS-KS-CM) (12.1-21.4 ng/ml). In contrast, small amounts of bFGF were detected in AIDS-KS-CM (76-245 pg/ml). The combination of anti-VEGF and anti-bFGF IgGs completely inhibited endothelial cell growth-promoting activities in AIDS-KS-CM, while activities partially remained in the presence of anti-bFGF IgG or anti-VEGF IgG alone. VEGF and bFGF in AIDS-KS-CM were distinguished by heparin-affinity chromatography. Furthermore, the combination of VEGF and bFGF synergistically augmented the growth of endothelial cells. Both VEGF and bFGF revealed an angiogenic property that was inhibited by specific Abs, when applied to the rabbit cornea and chicken chorioallantoic membrane. On Western blots, anti-VEGF IgG gave two major bands of 22 and 24 kDa, similar to those of recombinant VEGF165. As detected on Northern blots, AIDS-KS cells expressed major 3.9-kb VEGF-specific mRNA. Thus, VEGF, in concert with bFGF, may play a crucial role in the angiogenesis of AIDS-KS lesions.