Tara M. Weitz

A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aβ, and frank neuronal loss.

Alzheimers disease (AD) is hallmarked by amyloid plaques, neurofibrillary tangles, and widespread cortical neuronal loss (Selkoe, 2001). The “amyloid cascade hypothesis” posits that cerebral amyloid sets neurotoxic events into motion that precipitate Alzheimer dementia (Hardy and Allsop, 1991). Yet, faithful recapitulation of all AD features in widely used transgenic (Tg) mice engineered to overproduce Aβ peptides has been elusive. We have developed a Tg rat model (line TgF344-AD) expressing mutant human amyloid precursor protein (APPsw) and presenilin 1 (PS1ΔE9) genes, each independent causes of early-onset familial AD. TgF344-AD rats manifest age-dependent cerebral amyloidosis that precedes tauopathy, gliosis, apoptotic loss of neurons in the cerebral cortex and hippocampus, and cognitive disturbance. These results demonstrate progressive neurodegeneration of the Alzheimer type in these animals. The TgF344-AD rat fills a critical need for a next-generation animal model to enable basic and translational AD research.

Microglia in Alzheimer's Disease: It's All About Context

Neuroinflammation is now regarded as both an early event and prime mover in the pathobiology of Alzheimer disease (AD), a neurodegenerative disease that represents a growing public health threat. As the resident innate immune cells within the central nervous system, microglia are centrally positioned as key orchestrators of brain inflammation. It is now accepted that numerous forms of activated microglia exist. Furthermore, while some types of reactive microglia are detrimental, others can actually be beneficial. In the context of AD etiopathology, much debate surrounds whether these enigmatic cells play “good” or “bad” roles. In this article, we distill a complex clinical and experimental literature focused on the contribution of microglia to AD pathology and progression. A synthesis of the literature only seems possible when considering context– the conditions under which microglia encounter and mount immunological responses to AD pathology. In order to carry out these diverse contextual responses, a number of key receptors and signaling pathways are variously activated. It will be critically important for future studies to address molecular mediators that lead to beneficial microglial responses and therefore represent important therapeutic targets for AD.

Multi-Shell Hybrid Diffusion Imaging (HYDI) at 7 Tesla in TgF344-AD Transgenic Alzheimer Rats

Diffusion weighted imaging (DWI) is widely used to study microstructural characteristics of the brain. Diffusion tensor imaging (DTI) and high-angular resolution imaging (HARDI) are frequently used in radiology and neuroscience research but can be limited in describing the signal behavior in composite nerve fiber structures. Here, we developed and assessed the benefit of a comprehensive diffusion encoding scheme, known as hybrid diffusion imaging (HYDI), composed of 300 DWI volumes acquired at 7-Tesla with diffusion weightings at b = 1000, 3000, 4000, 8000 and 12000 s/mm2 and applied it in transgenic Alzheimer rats (line TgF344-AD) that model the full clinico-pathological spectrum of the human disease. We studied and visualized the effects of the multiple concentric “shells” when computing three distinct anisotropy maps–fractional anisotropy (FA), generalized fractional anisotropy (GFA) and normalized quantitative anisotropy (NQA). We tested the added value of the multi-shell q-space sampling scheme, when reconstructing neural pathways using mathematical frameworks from DTI and q-ball imaging (QBI). We show a range of properties of HYDI, including lower apparent anisotropy when using high b-value shells in DTI-based reconstructions, and increases in apparent anisotropy in QBI-based reconstructions. Regardless of the reconstruction scheme, HYDI improves FA-, GFA- and NQA-aided tractography. HYDI may be valuable in human connectome projects and clinical research, as well as magnetic resonance research in experimental animals.

CSF MARKERS OF INFLAMMATION AND ALZHEIMER'S DISEASE PATHOGENESIS IN THE COGNITIVELY INTACT PREVENT-AD COHORT

cant decrease of human Tau multimers (HT7/HT7 setup), as well as a significant decrease of a misfolded Tau (MC-1/HT7 setup) in a total brain fraction.A trend to decrease humanTau phosphorylated at pS396 in different brain fractions was also observed. ACI-35 treatment significantly improved the rotarod performance in both the transgenic hTauP301S-Tg model and the AAV-TauP301S spreading model. Conclusions: The study demonstrated that active immunization with ACI-35 significantly decreased human pathological Tau species in different brain fractions and ameliorated the clinical phenotype in two different mouse models of tauopathy.

Bi-directional Association of Cerebrospinal Fluid Immune Markers with Stage of Alzheimer’s Disease Pathogenesis

Immune mechanisms may be important in the pathogenesis of Alzheimer’s disease (AD). Yet, studies comparing cerebrospinal fluid (CSF) and plasma immune marker levels of healthy and demented individuals have yielded conflicting results. We analyzed CSF from 101 members of the parental history-positive PREVENT-AD cohort of healthy aging adults, and 237 participants without dementia from the initial cohort of the Alzheimer’s Disease Neuroimaging Initiative (ADNI-1). Following recent practice, we used the biomarkers total-tau and amyloid-β1-42 to allocate participants from each study into four stages of AD pathogenesis: Stage 0 (no abnormality), Stage 1 (reduced amyloid-β1-42), Stage 2 (reduced amyloid-β1-42 and increased total-tau), or “Suspected Non-Alzheimer Pathology” (elevated total-tau only). Investigating the PREVENT-AD participants’ CSF assay results for 19 immune/inflammatory markers, we found six that showed a distinct bi-directional relationship with pathogenetic stage. Relative to Stage 0, these were diminished at Stage 1 but strongly increased at Stage 2. Among the ADNI participants (90 healthy controls and 147 with mild cognitive impairment), we found that 23 of 83 available CSF markers also showed this distinct pattern. These results support recent observations that immune activation may become apparent only after the onset of both amyloid and tau pathologies. Unexpectedly, they also suggest that immune marker activity may diminish along with earliest appearance of amyloid-β plaque pathology. These findings may explain discordant results from past studies, and suggest the importance of characterizing the extent of AD pathology when comparing clinical groups.

NANOPARTICLE TGF-β SIGNALING BLOCKADE IN TREM2+ PERIPHERAL MACROPHAGES ATTENUATES ALZHEIMER PATHOLOGY IN TGF344-AD RATS

P1-015 NANOPARTICLE TGF-b SIGNALING BLOCKADE IN TREM2 PERIPHERAL MACROPHAGES ATTENUATES ALZHEIMER PATHOLOGY IN TGF344-AD RATS Alicia M. Quihuis, Tara M. Weitz, Brian Pak Yan Leung, Dongin Kim, Javier Rodriguez, Jr. Tarek Fahmy, Terrence Town, University of Southern California, Los Angeles, CA, USA; Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, USA; Hong Kong University of Science and Technology, Hong Kong, Hong Kong; Texas A&M Irma Lerma Rangel College of Pharmacy, College Station, TX, USA; Yale University, New Haven, CT, USA. Contact e-mail: quihuis@usc.edu

INCREASED PRO-INFLAMMATORY SIGNALING AND EVIDENCE OF ALZHEIMER’S DISEASE PATHOLOGY IN HEALTHY OLDER ADULTS AT RISK FOR AD

and anti-asthmatic drug Montelukast elevated hippocampal neurogenesis, reduced neuroinflammation, and improved learning and memory.Methods:AsMontelukast is known to have a low bioavailability, we were now aiming to optimize the pharmacology of Montelukast by improving its formulation.Results:In a Phase I study, we demonstrated that an oral film formulation of Montelukast (Montelukast VersaFilm) is safe and tolerable in healthy subjects, reduces the first-pass-effect and has a 52% higher bioavailability compared to the regular Montelukast tablet. Of importance for any CNSactive drugs, we detected Montelukast in the cerebrospinal fluid of the Montelukast VersaFilm treated healthy volunteers clearly indicating blood brain barrier penetrance. Of note, Montelukast, in contrast to many other CNS penetrating drugs, has an excellent safety and tolerability profile.We are at this stage preparing a Phase II trial to demonstrate efficacy of the Montelukast VersaFilm to improve cognitive function in AD. Conclusions:Montelukast VersaFilm might be a novel effective therapeutic entering the field of Alzheimer’s Disease to improve cognitive function.

Quantitative 3D In Silico Modeling (q3DISM) of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease.

Neuroinflammation is now recognized as a major etiological factor in neurodegenerative disease. Mononuclear phagocytes are innate immune cells responsible for phagocytosis and clearance of debris and detritus. These cells include CNS-resident macrophages known as microglia, and mononuclear phagocytes infiltrating from the periphery. Light microscopy has generally been used to visualize phagocytosis in rodent or human brain specimens. However, qualitative methods have not provided definitive evidence of in vivo phagocytosis. Here, we describe quantitative 3D in silico modeling (q3DISM), a robust method allowing for true 3D quantitation of amyloid-β (Aβ) phagocytosis by mononuclear phagocytes in rodent Alzheimers Disease (AD) models. The method involves fluorescently visualizing Aβ encapsulated within phagolysosomes in rodent brain sections. Large z-dimensional confocal datasets are then 3D reconstructed for quantitation of Aβ spatially colocalized within the phagolysosome. We demonstrate the successful application of q3DISM to mouse and rat brains, but this methodology can be extended to virtually any phagocytic event in any tissue.

HARNESSING INNATE IMMUNITY TO TREAT ALZHEIMER'S DISEASE

Background: Generation of neurotoxic amyloid-ß peptides and their deposition along with neurofibrillary tangle formation represent key pathological hallmarks in Alzheimer’s disease (AD). Recent evidence suggests that inflammation may be a third important component which, once initiated in response to neurodegeneration or dysfunction actively contributes to disease progression and chronicity. Microglia is being activated by binding of aggregated proteins or aberrant nucleic acids to pattern recognition receptors which elicit an innate immune response. The latter is characterized by the release of in€ıflammatory mediators including complement activators and inhibitors, chemokines, cytokines, radical oxygen species and enzyme systems. Exogenous as well as endogenous factors may promote and facilitate neuroinflammation in the AD brain. Thus, degeneration of aminergic brain stem nuclei including the locus ceruleus and the nucleus basalis of Meynert may drive inflammation in their projection areas given the antiinflammatory and neuroprotective action of their key transmitters norepinephrine and acetylcholine. Methods: Analysis of neuroinflammatio and in particular of micro and astroglial cell function in vitro and in vivo. Determination of inflammatory markes from cell culture, murine mouse brain and brain tissue or cerebrospinal fluid of MCI and AD patients. Results: In inflammation may not just occur secondary to degeneration, but actively drive amyloid beta aggregation and APP processing. Inhibition of themicroglia driven innate immune response at key signalling steps may provide protection. Conclusions: Therefore, antiinflammatory treatment strategies should be considered. Data on microglial activation in AD along with suggestions to modify and alter the prointo an antiinflammatory phenotype will be reviewed and discussed.

Pharmacological blockade of TGF-beta signaling in peripheral macrophages mitigates Alzheimer's-like pathology in preclinical rodent models

(EMG) data were recorded from bipolar electrodes in the region of the anterior frontal cortex in thirteen male lemurs. The EEG analysis was focused on the differences between active and passive state (no sleep) during daytime only and on the correlation between cortical EEG markers and EMG activity during nighttime. Results: Fig.1 (top-left) shows the grand-average (N1⁄411) of the normalized EEG power density obtained averaging data recorded during the daytime for the two conditions (active, passive). Fig.1 (top-right) reports the individual values of the normalized EEG power density for the two conditions in eight frequency bands of interest The distributions did not show remarkable outliers. Finally, Fig.1 (middle) shows the mean values (6standard error) of the normalized EEG power density illustrating a statistical ANOVA interaction effect (p<0.00005) between the factors Condition and Band. Duncan planned post-hoc test disclosed that the normalized EEG power density at 1-2 Hz and 2-4 Hz was higher during the active state than during the passive state. Furthermore, it was lower during the active than during the passive condition at 6-8 Hz, 8-10 Hz, and 10-12 Hz (p<0.00005).A statistically significant positive correlation (Fig.1 bottom) was found between the mean rectified EMG activity and the normalized EEG power density at 2-4 Hz. On the contrary, a statistically significant negative correlation (Fig.1 bottom) was found between the mean rectified EMG activity and the normalized EEG power density at 8-10 Hz and 10-12 Hz.Conclusions: In conclusions, this is the first study showing peculiar on-going EEG markers of motor activity in gray mouse lemurs. These results and further studies will improve our understanding of the neurophysiological mechanisms underlying the motor activity and cortical arousal in this animal model and its use in drug discovery for Alzheimer’ disease.