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Alzheimer's disease (AD) is a member of a category of neurodegenerative diseases characterized by the conformational change of a normal protein into a pathological conformer with a high beta-sheet content that renders it resistant to degradation and neurotoxic. In the case of AD the normal soluble amyloid beta (sAbeta) peptide is converted into oligomeric/fibrillar Abeta. The oligomeric forms of Abeta are thought to be the most toxic, while fibrillar Abeta becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. In addition, the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is an essential part of the pathology. Many therapeutic interventions are under investigation to prevent and treat AD. The testing of these diverse approaches to ameliorate AD pathology has been made possible by the existence of numerous transgenic mouse models which each mirror different aspects of AD pathology. Perhaps the most exciting of these approaches is immunomodulation. Vaccination is currently being tried for a range of age associated CNS disorders with great success being reported in many transgenic mouse models. However, there is a discrepancy between these results and current human clinical trials which highlights the limitations of current models and also uncertainties in our understanding of the underlying pathogenesis of AD. No current AD Tg mouse model exactly reflects all aspects of the human disease. Since the underlying etiology of sporadic AD is unknown, the process of creating better Tg models is in constant evolution. This is an essential goal since it will be necessary to develop therapeutic approaches which will be highly effective in humans.

The pathogenesis of Alzheimer's disease (AD) is thought to be related to the accumulation of amyloid β (Aβ) in amyloid deposits and toxic oligomeric species. Immunomodulation is emerging as an effective means of shifting the equilibrium from Aβ accumulation to clearance; however, excessive cell mediated inflammation and cerebral microhemorrhages are two forms of toxicity which can occur with this approach. Vaccination studies have so far mainly targeted the adaptive immune system. In the present study, we have stimulated the innate immune system via the Toll-like receptor 9 (TLR9) with cytosine-guanosine-containing DNA oligodeoxynucleotides in Tg2576 AD model transgenic mice. This treatment produced a 66% and 80% reduction in the cortical (p= 0.0001) and vascular (p= 0.0039) amyloid burden, respectively, compared with nontreated AD mice. This was in association with significant reductions in Aβ42, Aβ40, and Aβ oligomer levels. We also show that treated Tg mice performed similarly to wild-type mice on a radial arm maze. Our data suggest that stimulation of innate immunity via TLR9 is highly effective at reducing the parenchymal and vascular amyloid burden, along with Aβ oligomers, without apparent toxicity.

the control group. After training, these differences in task-related cortical activation patterns between groups were reduced. Conclusions: The results of our study indicate that a computer assisted training program over 4 weeks may significantly improve visual working memory task-performance in healthy elderly and MCI patients and that this improvement is accompanied by neuroplastical changes, as indicated by altered task-related cortical activation patterns.

Immunotherapies for various neurodegenerative diseases have recently emerged as a promising approach for clearing pathological protein conformers in these disorders. This type of treatment has not been assessed in models that develop neuronal tau aggregates as observed in frontotemporal dementia and Alzheimer's disease. Here, we present that active immunization with a phosphorylated tau epitope, in P301L tangle model mice, reduces aggregated tau in the brain and slows progression of the tangle-related behavioral phenotype. Females had more tau pathology than males but were also more receptive to the immunotherapy. The tau antibodies generated in these animals recognized pathological tau on brain sections. Performance on behavioral assays that require extensive motor coordination correlated with tau pathology in corresponding brain areas, and antibody levels against the immunogen correlated inversely with tau pathology. Interestingly, age-dependent autoantibodies that recognized recombinant tau protein but not the immunogen were detected in the P301L mice. To confirm that anti-tau antibodies could enter the brain and bind to pathological tau, FITC-tagged antibodies purified from a P301L mouse, with a high antibody titer against the immunogen, were injected into the carotid artery of P301L mice. These antibodies were subsequently detected within the brain and colocalized with PHF1 and MC1 antibodies that recognize pathological tau. Currently, no treatment is available for clearing tau aggregates. Our present findings may lead to a novel therapy targeting one of the major hallmarks of Alzheimer's disease and frontotemporal dementia.

Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. The meningoencephalitis observed in the first AD vaccination trial was likely related to excessive cell-mediated immunity caused by the immunogen, amyloid-beta (Abeta) 1-42, and the adjuvant, QS-21. To avoid this toxicity, we have been using Abeta derivatives in alum adjuvant that promotes humoral immunity. Other potential side effects of immunotherapy are increased vascular amyloid and associated microhemorrhages that may be related to rapid clearance of parenchymal amyloid. Here, we determined if our immunization strategy was associated with this form of toxicity, and if the therapeutic effect was age-dependent. Tg2576 mice and wild-type littermates were immunized from 11 or 19 months and their behaviour evaluated prior to killing at 24 months. Subsequently, plaque- and vascular-Abeta burden, Abeta levels and associated pathology was assessed. The therapy started at the cusp of amyloidosis reduced cortical Abeta deposit burden by 31% and Abeta levels by 30-37%, which was associated with cognitive improvements. In contrast, treatment from 19 months, when pathology is well established, was not immunogenic and therefore did not reduce Abeta burden or improve cognition. Significantly, the immunotherapy in the 11-24 months treatment group, that reduced Abeta burden, did not increase cerebral bleeding or vascular Abeta deposits in contrast to several Abeta antibody studies. These findings indicate that our approach age-dependently improves cognition and reduces Abeta burden when used with an adjuvant suitable for humans, without increasing vascular Abeta deposits or microhemorrhages.

s / Neurobiology of Aging 35 (2014) 715–724 721 rescued the behavioral deficits, reduced the levels of Ab42 oligomers and amyloid plaques and ameliorated synapse loss, neuronal damage and astrogliosis. Conclusions. Utilizing a novel in vitro screening assay to block fibril growth we found that two FDA approved drugs that reduce the accumulation of Ab and ameliorate the Ab-associated pathology in APPtg mice, suggesting that these classes of compounds might have the potential for repositioning for AD applications. IMMUNOTHERAPY TARGETING TAU AND AMYLOID Ab PATHOLOGY IN AD ANIMAL MODELS Allal Boutajangout , Mahmoud Al-Ahwal , Hamid Habib , Thomas Wisniewski . New York Universiy, School of Medicine, New York, New York, USA; King Abdulaziz University, School of Medicine, Departments of Neurology and Neuroscience, Physiology and Psychiatry, Jeddah, Saudi Arabia; King Abdulaziz University, School of Medicine, Department of Pediatrics, Jeddah, Saudi Arabia; New Youk Universiy, School of Medicine, Departments of Neurology, Pathology and Psychiatry, NewYork, NewYork, USA Objectives. Emerging evidence suggests that effective therapy for AD requires targeting tau related pathology in addition to reducing amyloid plaques. We reported the first active and passive immunization studies targeting abnormal tau and showed that this prevents functional and cognitive impairments in ADmodel mice. Recently, we have demonstrated that a blocker of the Ab/apolipoprotein E (apoE) interaction, Ab12-28P, has a therapeutic effect on both tau and amyloid Ab related pathologies. Methods. Active Immunization with ptau: hTau/PS1 were immunized from 2-3 months of age with our ptau derivative. Three non-immunized control groups received alum adjuvant alone: 1) Identical mice that were not immunized; 2) hTau/PS1M146Lmice that expressedmouse tau, as well as; 3) hTau littermates on a mtau KO background. At 7-8 months, behavioral testing was done followed by tissue analysis. Passive Immunization with PHF1 antibody: Homozygous JNPL3 P301L mice (2-3 months) were injected intraperitoneally once per week with PHF1 or pooled mouse IgG for a total of 13 injections. Their behavior was assessed at 5-6 months of age and brain tissue subsequently harvested for analysis of treatment efficacy. Treatment with Ab12-28P: old triple transgenic animals (21 months) were injected intraperitoneally three times per week for 19 weeks. At 25 months the animals went through sensorimotor and cognitive tests followed by tissue analysis. Results. Immunized P301L mice with prophylactic active immunization produced a 52% reduction of tau pathology immunohistochemical. Treatment with the same immunogen in hTau/PS1 Tg mice, demonstrated a 57% reductionof taupathologyandpreventedcognitivedecline in threecognitive tests. Passive immunizationwith PHF1antibodyproduced a 58% reduction of taupathology in thedentate gyrus of the hippocampus (p1⁄40.02). ByWestern blots, the antibody therapy resulted in a reduced ratio of pathological to total tau by 27% (p1⁄40.001) and decrease functional impairments in P301L model mice. Treatment with Ab12-28P reduces tau pathology both immunohistochemicallyandbiochemically, aswell as reducing the amyloidburden,with suppression of activation of astrocytes andmicroglia. Cognitive tests showed that in treated Tgx3 ADwere significantly improved compared to control Tg mice (Two-way ANOVA: p

L’immunotherapie contre la maladie d’Alzheimer (MA) est une approche therapeutique tres prometteuse. En effet, chez les souris transgeniques, l’immunisation par le peptide amyloide β (Aβ1-42) induit une reponse immunitaire, ameliore la cognition et reduit la charge amyloide cerebrale. Cependant, une encephalopathie peut survenir chez certains patients. C’est pourquoi des derives de ce peptide sont actuellement testes comme nouveaux immunogenes afin de diminuer les risques inflammatoires. Objectifs notre but est d’etudier les effets du peptide modifie K6Aβ1-30 sur des microcebes âges qui peuvent developper des lesions de type Alzheimer. Ces animaux ont ete suivis via des controles sanguins, des etudes comportementales et des examens histologiques post mortem. Materiel et methodes trente-deux microcebes âges de 6-10 ans (temoins versus immunises) ont ete evalues par une tâche a choix multiples mettant en jeu la memoire spatiale : memorisation d’un trajet dans un labyrinthe. Le groupe immunise a ensuite recu 3 injections sous-cutanees de K6Aβ1-30 suivies de prelevements sanguins a differents temps post-injection afin de suivre la reponse immunitaire. Le comportement des animaux a ete teste en parallele. A la fin du protocole, des analyses neurohistologiques ont ete effectuees pour rechercher les lesions de type Alzheimer : plaques amyloides, proteine Tau agregee, gliose… Resultats Les microcebes âges presentent une bonne reponse immunitaire. De plus, 5 mois apres la derniere injection, la reponse immunitaire etait reversible en l’absence d’immunisation. L’analyse comportementale montre un maintien des competences mnesiques chez les animaux immunises. L’analyse neuropathologique montre une diminution des lesions corticales. Des plaques amyloides compactes ont ete detectees chez un animal temoin alors que chez un animal immunise les plaques etaient diffuses. Nous avons egalement observe une diminution de l’Aβ intracellulaire chez les microcebes immunises accompagnee d’une augmentation du nombre de neurones pyramidaux marques par la proteine tau normale. D’autre part, aucune microhemorragie n’a ete detectee chez les animaux et la presence de microglie est plus faible chez les immunises. Conclusion la vaccination par le peptide K6As1-30, bien toleree par les microcebes âges, va dans le sens d’une amelioration des performances cognitives et d’une diminution de la presence de marqueurs pathologiques.

Phosphorylated tau is deposited as insoluble inclusion bodies in the tauopathies. We have used a new efficient method to dephosphorylate tau extracted from control and tauopathy brain. In some tauopathies, including Alzheimer’s disease and progressive supranuclear palsy, the pattern of insoluble tau isoforms reflected that of soluble tau. In contrast, in corticobasal degeneration, Pick’s disease, and some forms of fronto-temporal dementia, specific tau isoforms were selectively sequestered into insoluble inclusion-forming tau. Therefore the overall expression of individual tau isoforms does not predict which tau isoforms are deposited in all tauopathies and different mechanisms must operate that result in the deposition of specific tau isoforms.