Faculty Bibliography

Background: We have shown that active immunization with a novel nonself amyloidogenic peptide (pABri) induced a humoral immune response, largely IgM, to both PHF and toxic Abeta species inAD model, APP/PS1 transgenic (Tg) mice. Histology revealed a lower amyloid burden in both the cortex and hippocampus, along with improved cognitive testing scores compared to controls. pABri immunization resulted in lower levels of soluble and insoluble Abeta42 and Abeta40 in Tg mice. Plasma from these mice was used to immunostain human AD temporal cortex brain tissue. Staining of cytoplasm and dendrites of neurons, paired helical filaments, and Abeta plaques was documented. Methods: The novel peptide, pABri, is a carboxyl fragment of an amyloidogenic protein which is deposited in the brain of patients with a rare autosomal dominant disease due to a missense mutation in a stop codon, resulting in the translation of an intronic sequence, with no known sequence homology to any mammalian protein. Hence, this immunomodulatory therapeutic is unlikely to produce autoimmune toxicity since it utilizes a non-self peptide. This current study utilizes the pABri peptide as an immunogen for active immunization in two other mouse AD Tg models: 3xTg, with tau and amyloid pathology, and TgSwDI, with extensive congophilic angiopathy. Toxicity, neuropathology, humoral immune responses, and cognitive behavior were assessed. Results: The antibodies produced are against both the primary sequence of the immunogen as well as to the pathology associated b-sheet structure that is shared by both NFTs and amyloid plaques. These conformationally specific antibodies, reacting to Abeta peptide and tau oligomers, are against a b-sheet conformation since the immunogen, pAbri, is predominantly in such a conformation. Treatment led to cognitive rescue with pABri matching cognition of WT mice. Brain homogenates revealed lower Abeta40 and Abeta42 levels in pABri treated 3xTg mice compared to controls. pABri treatment groups show lower amyloid bu!

HIV-ITP patients have a unique antibody (Ab) against platelet GPIIIa49-66 which induces oxidative platelet fragmentation in the absence of complement (Cell 106: 551, 2001; JCI 113: 973, 2004). The search for a physiologic ligand that could induce this reaction was undertaken by panning the GPIIIa49-66 peptide with a phage surface display 7-mer peptide library. From 20 positive clones, 1 had 70% identity with a C-terminal region of ADAMTS-18 (a disintegrin and metalloproteinase with thrombospondin (TSR)-like motif 18), which is secreted by endothelial cell (EC). The recombinant C-terminal fragment of ADAMTS-18 can completely dissolve platelet aggregates formed in vitro. Moreover, this fragment lyses thrombi formed in the cerebral artery of mice and reduces infarction and neurologic impairment in murine ischemic stroke model (Blood 113: 6051, 2009). However, whether ADAMTS-18 represents the dominant physiologic mechanism controlling thrombus dissolution in vivo remains to be clarified. Here, we used ADAMTS-18-deficient (ADAMTS-18^-/-) mice to study the contributions of ADAMTS-18 to thrombus formation in vivo. To investigate possible functional differences between WT and ADAMTS-18^-/- platelets, we tested WT and ADAMTS-18^-/- platelets in a model of pulmonary thromboembolism induced by infusion of a mixture of platelet agonist collagen (25 mug per mouse) and epinephrine (1 mug per mouse). In lung tissue Hematoxylin and eosin-stained (HE) slides, the mean number of thrombi per lung was same in the ADAMTS-18^-/- group compared with WT group (163.7 +/-14.38 vs 174.9 +/-11.73, n=30/group, P=0.5480). In vitro, there is no difference between WT and ADAMTS-18^-/- platelet aggregation trace and activation initiated by various platelet agonists ADP (10 muM) or collagen (2 mug/mL). No difference was noted on WT and ADAMTS-18^-/- platelet adhesion on immobilized ligand (fibrinogen). These results indicated ADAMTS-18 had no effect on platelet functio!

BACKGROUND: Central to the pathogenesis of Alzheimer's disease (AD) and many other neurodegenerative diseases is the conformational change of a normal self-protein into toxic oligomeric species and amyloid deposits. None of these disorders have an effective therapy, but immunization approaches hold great promise. We have previously shown that active immunization with a novel peptide when polymerized into a stable oligomeric conformation, pBri, induced a humoral immune response to toxic Abeta species in an AD model, APP/PS1 transgenic (Tg) mice, reducing plaque deposits. pBri is a glutaraldehyde polymerized form of the carboxyl fragment of an amyloidogenic protein, which is deposited in the brains of patients with a rare autosomal dominant disease due to a missense mutation in a stop codon, resulting in the translation of an intronic sequence, with no known sequence homology to any mammalian protein. METHODS: In the current study we tested whether pBri-peptide-based immunomodulation is effective at reducing both vascular amyloid deposits and tau-related pathology using TgSwDI mice with extensive congophilic angiopathy and 3xTg mice with tau pathology. RESULTS: Our results indicate that this immunomodulation approach, which produces a humoral response to proteins in a pathological conformation, is effective at reducing both Abeta and tau-related pathologies. CONCLUSIONS: This immunomodulatory approach has the advantage of using a non-self-immunogen that is less likely to be associated with autoimmune toxicity. Furthermore we found that it is able to target all the cardinal features of AD concurrently.

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.

Soluble amyloid-beta oligomers (Abetao) trigger Alzheimer's disease (AD) pathophysiology and bind with high affinity to cellular prion protein (PrP(C)). At the postsynaptic density (PSD), extracellular Abetao bound to lipid-anchored PrP(C) activates intracellular Fyn kinase to disrupt synapses. Here, we screened transmembrane PSD proteins heterologously for the ability to couple Abetao-PrP(C) with Fyn. Only coexpression of the metabotropic glutamate receptor, mGluR5, allowed PrP(C)-bound Abetao to activate Fyn. PrP(C) and mGluR5 interact physically, and cytoplasmic Fyn forms a complex with mGluR5. Abetao-PrP(C) generates mGluR5-mediated increases of intracellular calcium in Xenopus oocytes and in neurons, and the latter is also driven by human AD brain extracts. In addition, signaling by Abetao-PrP(C)-mGluR5 complexes mediates eEF2 phosphorylation and dendritic spine loss. For mice expressing familial AD transgenes, mGluR5 antagonism reverses deficits in learning, memory, and synapse density. Thus, Abetao-PrP(C) complexes at the neuronal surface activate mGluR5 to disrupt neuronal function.

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.

Individuals with autism demonstrate atypical gaze, impairments in smooth pursuit, altered movement perception and deficits in facial perception. The olivo-floccular neuronal circuit is a major contributor to eye movement control. This study of the cerebellum in 12 autistic and 10 control subjects revealed dysplastic changes in the flocculus of eight autistic (67%) and two control (20%) subjects. Defects of the oculomotor system, including avoidance of eye contact and poor or no eye contact, were reported in 88% of autistic subjects with postmortem-detected floccular dysplasia. Focal disorganization of the flocculus cytoarchitecture with deficit, altered morphology, and spatial disorientation of Purkinje cells (PCs); deficit and abnormalities of granule, basket, stellate and unipolar brush cells; and structural defects and abnormal orientation of Bergmann glia are indicators of profound disruption of flocculus circuitry in a dysplastic area. The average volume of PCs was 26% less in the dysplastic region than in the unaffected region of the flocculus (p<0.01) in autistic subjects. Moreover, the average volume of PCs in the entire cerebellum was 25% less in the autistic subjects than in the control subjects (p<0.001). Findings from this study and a parallel study of the inferior olive (IO) suggest that focal floccular dysplasia combined with IO neurons and PC developmental defects may contribute to oculomotor system dysfunction and atypical gaze in autistic subjects.