NOTE: MATERIALS EMBARGOED FOR RELEASE – KINDLY OBSERVE THE INDIVIDUAL EMBARGOS NOTED FOR EACH PRESENTATION. AT THE SPECIFIED TIME, LOCAL TIME IN VANCOUVER, PDT, IS 3 HOURS BEHIND NEW YORK, EDT.
Newswise — NEW YORK, JULY 15, 2012 – Experts from the Comprehensive Center on Brain Aging at NYU Langone Medical Center will present new research at The 2012 Alzheimer’s Association International Conference on Alzheimer’s Disease to be held in Vancouver, British Columbia, Canada, July 14 – July 19.
From basic discovery to clinical applications, NYU Langone Medical Center has been at the forefront of the diagnosis and treatment of Alzheimer’s disease since the 1970s. The Comprehensive Center on Brain Aging, founded upon the strengths of the Silberstein Alzheimer’s Institute, is devoted to research and clinical advances toward the toward the treatment and cure of all neurodegenerative diseases affecting cognition, movement and behavior. The Pearl I. Barlow Center for Memory Evaluation and Treatment is regarded as New York City’s most comprehensive clinical treatment center for memory disorders of all origins. While there is currently no cure for Alzheimer's disease, advances in research and the use of pharmacologic therapies and non pharmacologic modalities to treat patients with the disease are changing the way people live and promise hope for the future. Please consider the following presentations. Each presentation is embargoed per the information below.
SATURDAY, JULY 14 Non-Invasive Evaluation of Tau Targeted Immunotherapy: A Tract-Tracing Bolus Memri (POSTER) Benjamin Winthrop Little, BA, Department of PsychiatryEMBARGOED FOR SATURDAY, JULY 14, 12:30PM – 2:30 PMAlzheimer’s disease is defined by the presence of a progressive dementia, associated with 2 microscopic lesions: amyloid plaques, that are made of extracellular Abeta protein aggregates, and neurofibrillary tangles, that are made of intraneuronal aggregates of abnormally phosphorylated tau protein. The aggregation of this tau protein has been shown in previous studies to decrease the rate of axonal transport . Immunotherapy targeting hyperphosphorylated tau is arising as a promising prospect to mitigate the neurodegenerative effects of such tauopathies. To assess the effectiveness of such immunotherapies can often involve the use of non human subjects . However, Manganese-Enhanced Magnetic Resonance Imaging (MEMRI) permits the longitudinal study of neuronal function with minimal risk to the animal. We hypothesize that tract-tracing MEMRI in a mouse model of tau pathology should enable the non-invasive monitoring of various tau targeting therapies aimed at improving neuronal integrity. Our results showed a significant increase in maximal slope of manganese uptake, Sv, was observed in the mitral cell layer in treated JNPL3 mice .
SUNDAY, JULY 15# 30710 - Physician Intention to Screen for Dementia (POSTER)James E. Galvin, MD, MPH, professor, Departments of Neurology and Psychiatry, NYU Langone Medical CenterEMBARGOED FOR RELEASE UNTIL SUNDAY, JULY 15, 1-3:30pmLittle is known about the factors that influence dementia screening behaviors in primary care providers. We explored individual perceptions that lead PCPs intention to evaluate their patients for dementia. We hypothesized that the provider’s knowledge of dementia and prior medical practice involving other disease screening would predict their intention to evaluate patients for cognitive disorders. We were able to identify knowledge deficits and belief systems regarding how PCPs approach older adults. Recent graduates were more internet savvy and more likely to consider evaluation of the older adult for cognitive problems. We developed 2 behavior-specific predictive models. Consumer-driven practices are predicated by subjective norms, that is what the physician perceived to be the accepted level of care amongst his colleagues and community. This is in contrast to proactive screening which is predicated by the perceived benefits of screening outweighing the perceived barriers to such screening. These findings will allow us to develop, implement and assess interventions to increase physician awareness of early signs of disease. These findings will be critical to developing national screening programs for AD and related disorders.
# P1-043 - Remission of Pre-Mild Cognitive Impairment (MCI), Subjective Cognitive Impairment (SCI): A Two Year Prospective Study of Demographic and Behavioral Markers (POSTER) Barry Reisberg, MD, Ricardo Osorio, Asif Khan, Carol Torossian, Kamalika Roy, Istvan Boksay, Ohnmar Thwin, Naveen Khanzada, Pawan Kumar, Melanie Shulman, Iryna LobachEMBARGOED FOR RELEASE UNTIL SUNDAY, JULY 15, 1-3:30PMPre-Mild Cognitive Impairment (MCI), Subjective Cognitive Impairment (SCI) has been associated with worsening to MCI and Alzheimers Disease (Jessen et al., Arch Gen Psychiatry, 2010). In our study, persons with SCI had a 4.5 time greater risk of decline to MCI or dementia over 7-years, than subjects with no-cognitive impairment (NCI). There have apparently been no studies of SCI remission. Such studies might be of great relevance for AD prevention.
Non-Invasive Evaluation Of Tau Targeted Immunotherapy: A Tract-Tracing Bolus Memri (POSTER) Benjamin Winthrop Little, BA, Department of PsychiatryEMBARGOED FOR SUNDAY,JULY 15, 1:30 PM – 3:30 PM(For description please see Saturday, July 14)
#P1-143 - Specific In Vivo Detection of Amyloid Plaques in Transgenic Mice using Bi-functional USPIO Nanoparticles (POSTER ) JiaLin Li, Dung Minh Hoang, Hong Xu, Yanjie Sun, Andrew Wang, Youssef Zaim Wadghiri, Thomas Wisniewski EMBARGOED FOR RELEASE UNTIL SUNDAY, JULY 15, 1-3:30PMAmyloid plaques are a key pathological hallmark of Alzheimer’s disease (AD). Their visualization is important for the diagnosis of AD, monitoring disease progression and evaluation of the efficacy of therapeutic interventions. We were the first group to use ultra-small super-paramagnetic iron oxide (USPIO) nanoparticles coupled to an amyloid targeting peptide to visualize amyloid plaques. USPIO’s have been widely used in animal and human imaging, and have been found to be very safe. However, our approach, so far, has required intra-carotid or intra-femoral injection, with mannitol to break the blood brain barrier (BBB). In the current study we sought to develop and test non-toxic, bifunctional USPIO particles which could be introduced via the femoral vein, without mannitol.
MONDAY, JULY 16, 2012Cognitive Detection of Preclinical AD (POSTER) Hiuyan Lau; Stella Karantzoulis; Catherine E. Myers; Elizabeth Pirraglia; Yi Li; Ashita Gurnani; Lidia Glodzik; Helen Scharfman; Raymond P. Kesner ; Mony J. de Leon; Steven H. Ferris. EMBARGOED FOR RELEASE UNTIL MONDAY, JULY 16 1:00PM- 3:00PMBiomarkers such as amyloid beta (e.g. Aβ42) and hyperphosphorylated tau (e.g. pTau181) in cerebral spinal fluid (CSF) and hippocampal volume loss measured by magnetic resonance imaging (MRI) are useful for identifying cognitively normal elderly likely to have ”preclinical” Alzheimer’s disease (AD), but such methods are invasive and/or expensive. We investigated whether cognitive tasks dependent on brain regions affected in early AD can serve as proxies of AD biomarkers. Research indicates that the hippocampal formation (Hipp), are affected in preclinical AD. Therefore, we hypothesized that performance on a CA3/DG-dependent spatial pattern separation task (PST) and a Hipp/EC-dependent discrimination and generalization task (DGT) would be impaired in cognitively normal individuals with biomarker evidence for AD. Initial data was collected from 31 cognitively normal NYU Alzheimer’s Disease Center/Center for Brain Health participants who had MRI and who also provided CSF for longitudinal studies. In the PST, participants discriminated between two identical dots, one in a previously viewed location and one in a new location. In the DGT, participants learned to discriminate pairs of stimuli determined by shapes or colors in a discrimination phase, then had to generalize the “preferred” shapes and colors to novel stimuli in a generalization phase. The preliminary results are consistent with our hypothesis that cognitive tasks dependent on brain regions affected by early AD pathology may provide a non-invasive and cost-effective method to identify and track change in clinically normal individuals at high risk for progressing to the MCI and dementia stages of AD.
# P2-399 - Active Immune Intervention for Prionoses in Deer( POSTER)Thomas Wisniewski, Candace Mathiason, Kinlung Wong, Jeanette Hayes-Klug, Amy Nalls, Kelly Anderson, Veronica Estevez, Lucia Yim, David Brown, Jose Alejandro Chabalgoity, Edward Hoover and Fernando Goni EMBARGOED FOR RELEASE UNTIL MONDAY, JULY 16 , 1:00PM- 3:00PMPrionoses are transmissible, neurodegenerative disorders. Bovine spongioform encephalopathy (BSE) has crossed the species barrier to infect humans. Chronic wasting disease (CWD) infects large numbers of deer and elk, with the potential to infect humans. Currently no prionoses has an effective treatment. Previously, we have demonstrated we could prevent transmission of prions in a proportion of susceptible mice with a mucosal vaccine. Currently, we attempted to produce an immune response in animals naturally susceptible to CWD, white tail deer, which could inhibit transmission. Two vaccinated animals produced low antibody titers, two intermediate titers and one high titers of IgA and IgG anti-PrP. Both groups produced high titers of IgA and IgG against Salmonella. Six months post-infection 5 out of 6 controls and 3 out of 5 vaccinated showed histologically prion structures in the tonsils. A year post-infection one of the vaccinated animals remained prion free, with all controls being infected. The negative animal has the highest titers of IgA in saliva and IgG systemic against PrP. Immunoglobulins purified from saliva, feces and serum of this vaccinated deer reacts to PrPRes. Oral immunization can be used to overcome tolerance to self-PrP protein and produce a mucosal IgA and systemic IgG response to normal and conformational modified PrP in large mammals. High antibody titers might be enough to prevent transmission or to retard progression of PrP infection. This approach may lead to an effective anti-prion vaccine.
Circulating Abeta40 Influences Plasma BDNF Levels and White Matter Integrity (POSTER)Nunzio Pomara,MD, professor, Department of Psychiatry, NYU School of Medicine, director Geriatric Psychiatry,Nathan S. Kline Research InstituteAnilkumar Pillai, Jay Nierenberg, Stephen Ginsberg, John J Sidtis, Pankaj Mehta, Henrik Zetterberg, Kaj Blennow, Peter BuckleyEMBARGOED UNTIL MONDAY JULY 16, 1:00PM – 3:00PM Reductions in brain-derived neurotrophic factor (BDNF) have been implicated in the pathophysiology of Alzheimer’s disease (AD). Nevertheless, the factors influencing central and peripheral BDNF levels are still poorly understood. Cerebral microvascular endothelial cells are known to be a major source of BDNF with a rate of production far exceeding that of cortical neurons. Exposure of these cells to amyloid beta (Abeta), results in cell death or injury with significant reductions in BDNF secretion. Moreover, in rodents, infusion of Abeta40 into the carotid resulted in a disruption of endothelial cells, which was not observed with Abeta42. Plasma Aβ40 levels have also been associated with white matter hyperintense lesions (WMHI) on MRI scans in AD, an effect that may be mediated by the toxic effects of soluble Aβ40 on small cerebral blood vessels and endothelial cells. Therefore, we hypothesized that concentrations of plasma Abeta40, but not Abeta42, would have a negative effect on plasma BDNF and on measures of white matter integrity as determined by Diffusion Tensor Imaging (DTI). To test this hypothesis, we examined BDNF and Abeta levels in plasma from 119 subjects with intact cognition (no dementia and a Mini-Mental State Exam score of at least 28) and no gross MRI abnormalities other than white matter hyperintensities. Of these, 88 subjects also had BDNF in plasma determined. Consistently with our prediction, Abeta40 was inversely correlated with BDNF concentrations (p<.001), whereas Abeta42 was independent (p=.231). Fractional anisotropy (FA; a measure of white matter integrity in DTI) was also inversely correlated with Abeta40 (p=.001) and so was performance in delayed recall (p=.029). In cognitively intact individuals, circulating Abeta40 results in reduction in plasma BDNF, white matter integrity (FA) and memory performance. As such, it may have prognostic significance.
Innate Immunity Stimulation as a Novel Therapeutic Approach in Alzheimers DiseaseScholtzova H, Goni F, Pan J, Sun Y, Li J, Mehta PD, Wisniewski T.EMBARGOED UNTIL MONDAY, JULY 16, 1PM-3PM Alzheimer’s disease (AD) is the most common cause of dementia and has a major societal and economic impact. Immunomodulation has shown great promise as an AD therapy, even though the initial clinical trial was associated with severe adverse effects in a minority of patients. Our research group postulated stimulation of the innate immune system, via the Toll-like receptor 9 (TLR9), as a possible alternative method for ameliorating AD pathology, without associated toxicity. A significant concern with immunotherapy is clearance of vascular amyloid and associated microhemorrhages. This is an important issue, since cerebral amyloid angiopathy (CAA) is a common feature in AD and cognitively normal elderly individuals. We tested the efficacy of TLR9 signaling stimulation for reducing parenchymal and vascular amyloid, as well as tau related pathology. Overall, stimulation of the TLR9 and thus innate immunity with CpG ODN (currently used in clinical trials for a variety of other diseases) represents a novel immunotherapeutic approach for AD.
TUESDAY, JULY 17, 2012Cellular and Molecular Mechanisms 6: NeuropathologyLongitudinal Reductions In Blood Pressure in Hypertensive Individuals is Associated With Increased Levels of Biomarkers For Alzheimer’s Disease (Oral Presentation)Lidia Glodzik MD,PhD, Henry Rusinek PhD, Pauline McHugh MD, Elizabeth Pirraglia MA, Schantel Williams RN, Megan Cummings, Yi Li MD, Kenneth Rich MD, Catherine Randall MA, Lisa Mosconi PhD, Ricardo Osorio MD, Henrik Zetterberg MD, PhD, Kaj Blennow MD, Mony de Leon EdDEMBARGOED UNTIL TUESDAY, JULY 17, 3:30PM – 5:00PMIn hypertension, cerebral blood flow regulation limits are changed and the blood pressure threshold at which CBF is safely maintained is higher. This shift may increase the brain’s vulnerability to hypoperfusion at lower blood pressure. Despite growing recognition of the link between hypoperfusion and neurodegeneration, little is known about whether blood pressure reductions can induce deficient perfusion and promote expression of cerebrospinal fluid (CSF) biomarkers of amyloid and neurofibrillary pathology. We investigated the relationship between longitudinal changes in mean arterial pressure (MAP) and CSF biomarkers of Alzheimer’s disease in a group of cognitively healthy elderly with and without hypertension. In subjects with HTN, MAP reduction is associated with increased CSF p-tau181 and deterioration of episodic memory, possibly resulting from suboptimal perfusion and subsequent accumulation of neurofibrillary tangles. Prior experimental work has demonstrated a relationship between perfusion, energetic reductions and tauopathy.
#30698 - The AD8 Dementia Screening Test Detects Mild Cognitive Impairment (POSTER)James Galvin, MD, MPH, professor, Departments of Neurology and Psychiatry, NYU Langone Medical CenterEMBARGOED UNTIL TUESDAY JULY 17Detection of mild cognitive impairment (MCI) and early-stage Alzheimer’s disease (AD) can be done either by comparing individual cognitive performance with normative values or assessing cognitive decline within an individual. The AD8 is a widely used, validated, 8-item dementia screening tool; endorsement of >2 questions suggests cognitive impairment. The AD8 may improve detection of MCI and early-stage dementia in clinical practice and enrollment into MCI clinical trials. 810 individuals were evaluated at the Washington University Knight Alzheimer’s Disease Research Center. Participants underwent identical assessments including all items from the Uniform Data Set, Clinical Dementia Rating (CDR) and Sum Boxes (CDR-SB). The AD8 questions were embedded throughout the interview. The AD8 detected the very mildest forms of cognitive impairment due to AD. Cut-off scores 2-5 suggest MCI and cut-off scores >5 suggest AD. Higher AD8 scores correlated with more impaired ratings in clinical, cognitive, functional and behavioral domains and MCI does indeed affect everyday functioning. Thus, if simple and efficient screening for MCI in applied settings is the goal the AD8 could be recommended on the basis of utility and brevity.
#P3-068 - Topic: Molecular And Cellular Processes And Pathologies Loss Of Antioxidant Peroxiredoxin 6 Protein Exacerbates In Vivo Neurodegeneration in Prion Disease. (POSTER)Ayodeji. A. Asuni, Maitea Guridi Ormazabal, Sandrine Sanchez, and Martin Sadowski.EMBARGOED UNTIL TUESDAY, JULY 17, 1PM – 3:30PM In Alzheimer’s disease (AD) synapse loss is more closely correlated with cognitive impairment than are plaques and tangles. We and others have extensively described similar synapse-specific vulnerability in the ME7-model of prion disease. This provides an excellent in vivo model in which to study hippocampus specific, synaptic degeneration and other degenerative components akin to the plethora of neurochemical and inflammatory changes associated with neurodegenerative diseases, like AD. Concomitantly there is an increase in astrocytes as disease progresses; with their extended processes closely associated with neuronal processes, synapses and blood vessels, where they can impact on brain energetics and cellular homeostasis as well as antioxidant levels. Recent evidence suggests that astrocytes play an active role in brain function and information processing, during development, aging and in pathology.
WEDNESDAY, JULY 18 Session 04-06 “Therapeutics/Therapeutic Strategies 2: Immunization:Mechanisms of Action and Alternative Approaches.” Active Immunomodulation Targeting Abnormal Conformation for the Treatment of Multiple Neurodegenerative Diseases (Oral Presentation)Fernando Goni, PhD, adjunct associate professor; adjunct associate professor, Department of Neurology, Division of Aging and Dementia Kinlung Wong, Henrieta Scholtzova, Yanjie Sun , Jason Pan, JiaLin Li, Yong Ji, Thomas WisniewskiEMBARGOED UNTIL WEDNESDAY, JULY 18, 11:30 AM– 1:00PMAlzheimer’s Disease (AD) is the most common of the conformational neurodegenerative disorders (NDD), and prion disease the most transmissible NDD. No highly effective treatment is currently available for any NDD. Previously, we showed that mutated Aβ peptides soluble and devoid of Tcell epitopes, produced a response correlated with amelioration of AD pathology in animal models. Our lab has demonstrated that active immunization with antigens mimicking abnormal conformations, such as polymerized ABri (pABri), could elicit antibody responses to oligomerized Aβ and conformational aberrant hyperphosphorylated tau (ptau). We have now tested a combined vaccination using pBri and mutated Aβ (pAβ) in 3xTg mice and human PrPTg animals. In the 3xTg mice the immunized animals showed no difference in locomotor activity to controls but a significant (p0.01) behavioral rescue by radial arm maze testing. The animals produced significant titers of IgM and IgG against oligomerized Aβ42. Histological analysis showed a significant reduction of both amyloid and tau pathology. Biochemically, the soluble ptau was shown to be substantially and significantly reduced. In HuPrPTg animals a systemic IgM and IgG response against polymerized PrP was observed, similar to the systemic one obtained in our oral PrP inoculations. pBri conformational vaccination can be used to elicit antibodies that recognize multiple pathological proteins, including PrPRes, oligomer A and ptau. In 3x Tg mice with both A and tau pathology and vaccinated with the combinatorial pABri+pAβ1-30KK, each of these pathologies were reduced histologically and biochemically, leading to behavioral rescue. Such a combined approach targeting individually aberrant Aβ and tau, and probably its patho-metabolical relationship would be much more likely to be efficacious in AD patients.
A Chorus for Older Adults with Dementia and their Family Members: Results of a Pilot Study (POSTER) Mary S. Mittelman, Dr.PH, research professor, Department of Psychiatry, Division of Brain Aging, NYU Langone Medical Center, Cynthia Epstein, LCSW, Concetta Tomaino, DA , Kendra Ray, MA and Jan Maier, RN, MPH, Department of PsychiatryEMBARGOED UNTIL WEDNESDAY JULY 18Few pleasurable group activities have been developed and tested for people with dementia together with their family members. We recently started a chorus for this population and conducted a pilot study of its benefits. We anticipated that singing and rehearsing together for a performance would provide an opportunity for the group to share a stimulating and social activity, and that the experience would improve the well-being and quality of life of all participants. To our knowledge, there have been no rigorous evaluations of the benefits of this kind of shared musical activity. Qualitative assessments included observation by a music therapist and NYU research staff, take-home questionnaires completed after the concert and focus groups. Eleven dyads participated. All but one attended every rehearsal. The majority of people with dementia improved from baseline to follow-up on self-rated quality of life, self-esteem, and communication with their family and friends. The majority of caregivers improved in health-related quality of life and social support. We now have evidence for the feasibility of the chorus and qualitative evidence of its efficacy. The information obtained by different approaches to data collection supported and enhanced the conclusion that the experience was validating and pleasurable for participants.
7 Tesla MR Susceptibility-Contrast Microscopy Imaging of Amyloid Pathology and Hippocampus in Alzheimer's Disease (POSTER)Yulin Ge, MD, associate professor, Department of Radiology, NYU Langone Medical Center, Yongxia Zhou, PhD, Jing Yang, MD, PhD, Yi Li, MD, Mony de Leon,EdD, Thomas Wisniewski, MD, Robert I. Grossman, MDEMBARGOED UNTIL WEDNESDAY, JULY 18, 2:00PM – 4:00PMAmyloid plaques are one of the hallmarks of Alzheimer’s disease (AD). Iron component in the immediate vicinity of amyloid plaques has been shown in animal studies of AD and acts as a source of reactive oxygen species for oxidative damage. Also, an interest in microstructural hippocampal imaging has emerged in recent years. Any imaging technique capable of directly visualizing amyloid plaques and fine hippocampal structures is critical for early and accurate diagnosis of AD. This work is to evaluate imaging parameters on 7T MR using SWI without any contrast agent to better identify the histopathologic correlate of amyloid plaques containing iron and otherwise invisible subhippocampal structures of human postmortem brain in patients with AD.Our data suggests that SWI on ultrahigh field strength MR has exhibited great potential to detect diminutive susceptibility contrast associated with iron and otherwise invisible fine hippocampal structures with near histopathologic resolution. Our findings concur with studies of AD transgenic mouse models that have previously correlated "susceptibility stains" with iron-containing amyloid plaques, which has not been confirmed in humans. SWI may provide a noninvasive direct detection and quantification of amyloid plaques in live human brain on ultra-high-field MR, and may become feasible in the near future. Due to markedly enhanced susceptibility contrast at ultra-high-field MR, it is possible to detect amyloid plaques associated with iron deposition using susceptibility weighted imaging in vivo in patients with AD.
"Novel Approaches to APP Therapeutic Modulation." An APP Translation Modulator ARN2966 Reduces Aß Deposition and Prevents Memory Deficit in AD Transgenic Mice (Oral Presentation)Martin Sadowski, MD, PhD, assistant professor, Departments of Neurology, Psychiatry and Biochemistry and Molecular Pharmacology, NYU Langone Medical CenterEMBARGOED UNTIL WEDNESDAY, JULY 18, 9:10AM -9:30AM Accumulation of amyloid-Aß (Aß) peptide in the brain is central to the pathogenesis of Alzheimer’s disease (AD). Development of anti-Aß therapies have been advocated for AD prevention and for the treatment during early stages of the disease when Aß toxicity still significantly influences neurodegenerative cascade including synaptotoxicity, neurofibrillary pathology, and neuronal loss. Aß production can be decreased by modulating processing or translation of the amyloid precursor protein (APP). While development of APP secretases inhibitors and anti-Aß immunization approaches are widely pursued, very few molecules capable of modulating APP expression and showing drug development potential have been identified thus far. Our studies demonstrate potential of using APP translation modulator as a therapeutic approach for AD and characterize a novel, BBB permeable therapeutic compound with strong potential for further preclinical development.
Session: 04-06 - Immunization Targeting a Minor Plaque Constituent Clears ß-Amyloid and Rescues Behavioral Deficits in an Alzheimer’s Disease Mouse Model (Oral Presentation)Jose Morales-Corraliza, PhD, Nathan Kline Institute Stephen Schmidt, Matthew Mazzella, Jason D. Berger, Donald Wilson, Daniel Wesson, Mathias Jucker, Efrat Levy, Ralph Nixon, Paul MathewsEMBARGOED UNTIL JULY 18, 11:30AM-1PM Anti-human-Aβ immunotherapy has been shown to clear brain β-amyloid plaques in β-amyloid depositing mouse models and in human Alzheimer’s disease (AD) brain. While immunotherapy targeting a minor constituent of peripheral amyloidoses has been shown to result in a broad amyloid clearance, targeting a minor brain plaque constituent leading to β-amyloid clearance has not been demonstrated. This immunization resulted in the clearance of more than one-half of the β-amyloid plaque pathology – including both the endogenous murine Aβ and the human Aβ components – following two months of treatment. The immunized mice additionally showed improvements in two behavioral assays, odor habituation and nesting behavior. We conclude that passive anti-murine-Aβ immunization clears β-amyloid plaque pathology – including the major human Aβ component – and decreases behavioral deficits, arguing that targeting minor, endogenous brain plaque constituents can be beneficial, broadening the range of plaque-associated targets for AD therapeutics.
Interplay of Dietary Cholesterol, Neuronal Endosomal Function, and Cholinergic Degeneration (POSTER)Paul MathewsEMBARGOED UNTIL WEDNESDAY, JULY 18, 2:00PM – 4:OOPMTHURSDAY, JULY 19, 2012
Repression of Eif2α Phosphorylation Via Conditional Deletion of PERK Alleviates Synaptic Plasticity And Spatial Memory Impairments In APP/PS1 Mice (Oral Presentation)Tao Ma, MD, PhD Mimi A. Wong, Douglas R. Cavener, and Eric KlannEMBARGOED UNTIL THURSDAY, JULY 19, 11:30AM – 1:00PM Eukaryotic initiation factor 2 (eIF2) plays a key role in the regulation of protein synthesis. Phosphorylation of α subunit of eIF2 (eIF2α) inhibits general mRNA translation and reduction of eIF2α phosphorylation lowers the threshold for the induction of long-lasting long-term potentiation (LTP). Four protein kinases have been identified thus far as eIF2 kinases. Here taking advantage of a mutant mouse model in which eIF2 kinase PERK is conditionally removed in the forebrain late in development (PERK cKO), we explored whether repression of eIF2α phosphorylation could alleviate synaptic dysfunction and memory deficits associated with Alzheimer’s disease (AD). Our findings indicate that AD-associated impairments in synaptic plasticity and memory can be prevented by decreasing PERK-dependent eIF2 phosphorylation, which might be linked to enhanced translation. These studies suggest that PERK and eIF2a are viable therapeutic targets for synaptic dysfunction in AD.
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