Faculty Bibliography

Desmosterol is a C27 sterol intermediate in cholesterol synthesis generated during the metabolic pathway that transforms lanosterol into cholesterol. It has become of particular interest in the pathogenesis of Alzheimer's disease (AD) because of the report that the activity of the gene coding for the enzyme DHCR24, which metabolizes desmosterol to cholesterol, is selectively reduced in the affected areas of the brain. Any change in the pattern of C27 sterol intermediates in cholesterol synthesis merits investigation with respect to the pathogenesis of AD, since neurosteroids such as progesterone can modulate the tissue levels. We therefore analyzed the C27 sterol composition using a metabolomics approach that preserves the proportion of the different sterol intermediates. In AD, the proportion of desmosterol was found to be less than that of age-matched controls. The findings do not directly support the focus on Seladin-1, although they could reflect different stages of a slowly progressive disease.

Amyloid plaques are a key pathological hallmark of Alzheimer's disease (AD). The detection of amyloid plaques in the brain is important for the diagnosis of AD, as well as for following potential amyloid targeting therapeutic interventions. Our group has developed several contrast agents to detect amyloid plaques using magnetic resonance microimaging (microMRI) in AD transgenic mice, where we used mannitol to enhance blood brain barrier (BBB) permeability. In the present study, we used bifunctional ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, chemically coupled with Abeta1-42 peptide to image amyloid plaque deposition in the mouse brain. We coupled the nanoparticles to polyethylene glycol (PEG) in order to improve BBB permeability. These USPIO-PEG-Abeta1-42 nanoparticles were injected intravenously in AD model transgenic mice followed by initial and subsequent muMRI. A 3D gradient multi-echo sequence was used for imaging with a 100 microm isotropic resolution. The amyloid plaques detected by T2*-weighted muMRI were confirmed with matched histological sections. The region of interest-based quantitative measurement of T2* values obtained from the muMRI showed contrast injected AD Tg mice had significantly reduced T2* values compared to wild-type mice. In addition, the scans were examined with voxel-based analysis (VBA) using statistical parametric mapping (SPM) for comparison of USPIO-PEG-Abeta1-42 injected AD transgenic and USPIO alone injected AD transgenic mice. The regional differences seen by VBA in the USPIO-PEG-Abeta1-42 injected AD transgenic correlated with the amyloid plaque distribution histologically. Our results indicate that USPIO-PEG-Abeta1-42 can be used for amyloid plaque detection by intravenous injection without the need to co-inject an agent which increases permeability of the BBB. This technique could aid the development of novel amyloid targeting drugs by allowing therapeutic effects to be followed longitudinally in model AD mice.

The relationship between the apolipoprotein E (ApoE) epsilon4 genotype and an increased risk of developing Alzheimer's disease (AD) has been well established in Caucasians but is less established among other ethnicities. ApoE epsilon4 has also been associated with several other neurological disorders. Whether ApoEpsilon4 epsilon4 is a risk factor for frontotemporal dementia (FTD) remains controversial. This study examined 432 patients with AD, 62 with FTD, and 381 sex- and age-matched controls. The ApoE epsilon4 allele frequency was significantly increased among patients in the AD and FTD groups compared with controls. The frequency of the ApoEpsilon epsilon4 allele was 24.86% in late-onset AD (p < 0.01), 18.02% in early-onset AD (p < 0.01), 16.13% in FTD (p < 0.01), and 7.34% in controls. ApoEpsilon epsilon4 prevalence was similar in the FTD and AD groups. The present study suggests that the ApoE epsilon4 allele is a risk factor for both disorders. (c) 2013 S. Karger AG, Basel.

Alzheimer's disease (AD) is the leading cause for dementia in the world. It is characterized by two biochemically distinct types of protein aggregates: amyloid beta (A beta ) peptide in the forms of parenchymal amyloid plaques and congophilic amyloid angiopathy (CAA) and aggregated tau protein in the form of intraneuronal neurofibrillary tangles (NFT). Several risk factors have been discovered that are associated with AD. The most well-known genetic risk factor for late-onset AD is apolipoprotein E4 (ApoE4) (Potter and Wisniewski (2012), and Verghese et al. (2011)). Recently, it has been reported by two groups independently that a rare functional variant (R47H) of TREM2 is associated with the late-onset risk of AD. TREM2 is expressed on myeloid cells including microglia, macrophages, and dendritic cells, as well as osteoclasts. Microglia are a major part of the innate immune system in the CNS and are also involved in stimulating adaptive immunity. Microglia express several Toll-like receptors (TLRs) and are the resident macrophages of the central nervous system (CNS). In this review, we will focus on the recent advances regarding the role of TREM2, as well as the effects of TLRs 4 and 9 on AD.

Platelets play a supportive role in tumor metastasis. Impairment of platelet function within the tumor microenvironment may provide a clinically useful approach to inhibit metastasis. We developed a novel humanized single-chain antibody (scFv Ab) against integrin GPIIIa49-66 (named A11) capable of lysing activated platelets. In this study, we investigate the effect of A11 on the development of pulmonary metastases. In the Lewis lung carcinoma (LLC) metastatic model, A11 decreases the mean number of surface nodules and mean volume of pulmonary nodules. It protects against lung metastases in a time window that extended 4 hours prior to and 4 hours after the i.v. injection of LLCs. Co-injection of GPIIIa49-66 albumin reverses the anti-metastatic activity of A11 in B16 melanoma model, consistent with the pathophysiological relevance of the platelet GPIIIa-49-66 epitope. Significantly A11 had no effect on angiogenesis using both in vitro and in vivo assays. The underlying molecular mechanisms are a combination of inhibition of each of the following interactions: between activated platelets and tumor cells, platelets and endothelial cells, and platelets and monocytes, as well as disaggregation of an existing platelet/tumor thrombus. Our observations may provide a novel anti-metastatic strategy through lysing activated platelets in the tumor microenvironment using humanized anti-GPIIIa49-66 scFv Ab.

Amyloid-beta (Abeta) oligomers are thought to trigger Alzheimer's disease pathophysiology. Cellular prion protein (PrP(C)) selectively binds oligomeric Abeta and can mediate Alzheimer's disease-related phenotypes. We examined the specificity, distribution and signaling of Abeta-PrP(C) complexes, seeking to understand how they might alter the function of NMDA receptors (NMDARs) in neurons. PrP(C) is enriched in postsynaptic densities, and Abeta-PrP(C) interaction leads to Fyn kinase activation. Soluble Abeta assemblies derived from the brains of individuals with Alzheimer's disease interacted with PrP(C) to activate Fyn. Abeta engagement of PrP(C)-Fyn signaling yielded phosphorylation of the NR2B subunit of NMDARs, which was coupled to an initial increase and then a loss of surface NMDARs. Abeta-induced dendritic spine loss and lactate dehydrogenase release required both PrP(C) and Fyn, and human familial Alzheimer's disease transgene-induced convulsive seizures did not occur in mice lacking PrP(C). These results delineate an Abeta oligomer signal transduction pathway that requires PrP(C) and Fyn to alter synaptic function, with deleterious consequences in Alzheimer's disease.