Faculty Bibliography

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.

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 CD40 receptor-CD40 ligand (CD40-CD40L) interaction has been shown to affect both immune and non-immune cells and is implicated in diverse activities including immunoglobulin class switching (IgM to IgG), atherosclerosis, chronic inflammation and Alzheimer's disease pathogenesis. A number of groups have studied the role of CD40 in prion disease, however, the results are conflicting presumably due to the use of different scrapie agent-host strain combinations and routes of infection. In the current study, we clarify the effect of CD40 on: (i) replication, progression to clinical disease, PrP(Sc) profile, and neuropathology associated with infection of a single host genotype with three distinct mouse-adapted scrapie strains, and (ii) the immune response of double knockout (PrP, CD40) transgenic mice to recombinant PrP as assessed by the generation of anti-PrP antibodies. Our results suggest that CD40: (i) results in slower disease progression and scrapie strain-specific differences in incubation periods, (ii) does not affect the level of scrapie strain-specific PrP(Sc), (iii) does not influence disease-associated neuropathology, but (iv), as expected, is required to mount an immune response generating anti-PrP IgG antibodies.