Experimental basis for generating nonhuman primate models of frontotemporal dementia and Alzheimer's disease.

Tau Pathology Generated by Overexpression of Tau

Shifting balance from neurodegeneration to regeneration of the brain: a novel therapeutic approach to Alzheimer's disease and related neurodegenerative conditions.

Increasing evidence points to soluble assemblies of aggregating proteins as a major mediator of neuronal and synaptic dysfunction. In Alzheimer disease (AD), soluble amyloid-beta (Abeta) appears to be a key factor in inducing synaptic and cognitive abnormalities. Here we report the novel finding that soluble tau also plays a role in the cognitive decline in the presence of concomitant Abeta pathology. We describe improved cognitive function following a reduction in both soluble Abeta and tau levels after active or passive immunization in advanced aged 3xTg-AD mice that contain both amyloid plaques and neurofibrillary tangles (NFTs). Notably, reducing soluble Abeta alone did not improve the cognitive phenotype in mice with plaques and NFTs. Our results show that Abeta immunotherapy reduces soluble tau and ameliorates behavioral deficit in old transgenic mice.

Functional Neurobiology of Aging

Nonhuman primates have been used as animal models in which to study cognitive changes associated with aging and age-related disease for decades. There are many advantages to using nonhuman primates for studies of aging including the capability to examine visual nonspatial cognitive processes and the ability to use operationally similar behavioral tasks to what is used with humans. Because some aspects of aging in humans do not develop naturally in nonhuman primates or do not follow the same course of natural development in monkeys, experimental models are necessary for some investigations. Research in our laboratory has identified similarities in the cognitive profiles of nonhuman primate models of aging, Alzheimer Disease, and menopause with their human counterparts. In addition, through the use of a variety of different techniques we have used these nonhuman primate models to begin to determine the neural substrates of age-related cognitive dysfunction noted with advanced age and age-related disease. In this paper, we review our observations made in nonhuman primate models of aging, Alzheimer Disease, and menopause and indicate areas for future research.

Regional distribution of cortical microglia parallels that of neurofibrillary tangles in Alzheimer's disease

The microtubule (MT) instability observed in Alzheimer's disease (AD) is commonly attributed to hyperphosphorylation of the MT-associated protein, tau. In vivo PET imaging offers an opportunity to gain critical information about MT changes with the onset and development of AD and related dementia. We developed the first brain-penetrant MT PET ligand, [11C]MPC-6827, and evaluated its in vivo imaging utility in vervet monkeys. Consistent with our previous in vitro cell uptake and in vivo rodent imaging experiments, [11C]MPC-6827 uptake increased with MT destabilization. Radioactive uptake was inversely related to (cerebrospinal fluid) CSF Aβ42 levels and directly related to age in a nonhuman primate (NHP) model of AD. Additionally, in vitro autoradiography studies also corroborated PET imaging results. Here, we report the preliminary results of PET imaging with [11C]MPC-6827 in four female vervet monkeys with high or low CSF Aβ42 levels, which have been shown to correlate with the Aβ plaque burden, similar to humans.

Lack of Tau Proteins Rescues Neuronal Cell Death and Decreases Amyloidogenic Processing of APP in APP/PS1 Mice

In total, 47,500,000 people worldwide are affected by dementia and this number is estimated to double by 2030 and triple within 2050 resulting in a huge burden on public health. Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia, accounting for 60-70% of all the cases. The cause of AD is still poorly understood but several brain abnormalities (e.g., loss of neuronal connections and neuronal death) have been identified in affected patients. In addition to the accumulation of β-amyloid plaques in the brain tissue, aberrant phosphorylation of tau proteins has proved to increase neuronal death.DYRK1A phosphorylates tau on 11 different Ser/Thr residues, resulting in the formation of aggregates called 'neurofibrillary tangles' which, together with amyloid plaques, could be responsible for dementia, neuronal degeneration and cell death. Small molecule inhibition of DYRK1A could thus represent an interesting approach toward the treatment of Alzheimer's and other neurodegenerative diseases. Herein we review the current progress in the identification and development of DYRK1A inhibitors.

Alzheimer's disease (AD) is characterized by the presence of neuropathological lesions containing amyloid plaques (APs) and hyperphosphorylated Tau containing neurofibrillary tangles (NFTs) and is associated with neuroinflammation and neurodegeneration. Entorhinal cortex (Brodmann's area 28) is involved in memory associated functions and is one of the first brain areas targeted to form the neuropathological lesions and also severely affected cortical region in AD. Glia maturation factor (GMF), a central nervous system protein and a proinflammatory molecule is known to be up-regulated in the specific areas of AD brain. Our previous immunohistochemical studies using temporal cortex showed that GMF is expressed in the vicinity of APs and NFTs in AD brains. In the present study, we have analyzed the expression of GMF and its association with APs and NFTs in the entorhinal cortex of AD brains by using immunohistochemistry combined with thioflavin-S fluorescence labeling methods. Results showed that GMF immunoreactive glial cells, glial fibrillary acidic protein labeled reactive astrocytes and ionized calcium binding adaptor molecule-1 labeled activated microglia were increased in the entorhinal cortical layers especially at the sites of 6E10 labeled APs and Tau containing NFTs. In conclusion, increased expression of GMF by the glial cells in the entorhinal cortex region, and the co-localization of GMF with APs and NFTs suggest that GMF may play important proinflammatory roles in the pathogenesis of AD.

The objective of this work was to develop a biophysical model that would elucidate the role of the brain neurofibrillary tangles (NFTs) play in the development of Alzheimer's disease (AD). AD is a devastating neurodegenerative disease, and this study [the study of Ian] is not only of substantial societal impact, but it will also contribute to the multidisciplinary efforts aimed at early detection, understanding factors behind disease progression and possibly personalized treatment of the disease. AD affects approximately 6.2 million Americans and is expected to grow exponentially by 2050 as the population ages. Those with AD required 15.3 billion hours of care, most of which is unpaid care from family members, and costs, on average, $321,780 per person. Current hypotheses on the mechanism of AD incorporate the combined role of two proteins: beta amyloid plaques and NFTs. They are hypothesized to work together in the amyloid cascade hypothesis to bring about the toxic effects of disease. The tau protein normally stabilizes microtubules in the central nervous system, but its phosphorylation causes destabilization and the formation of tangles. The direct cause of this phosphorylation is unknown, but amyloid plaques are believed to play a role. These tangles disrupt neuron function and synaptic communication. Unable to communicate, these cells die. The tangles propagate via synapticsynaptic connections, resulting in neuronal dysfunction, eventually cell death and thus regional atrophy which follows the pattern of NFTs. Cognitive decline increases as the disease worsens, generally thought to correlate with increasing spread of NFTs. Currently, AD is only able to be definitively diagnosed at autopsy, complicating the understanding of the disease and validation of therapeutic clinical trials. The advent of amyloid- and tau-specific PET tracers in conjunction with other imaging biomarkers has led to a hypothetical model of the progression of AD. However, the mechanism of propagation of disease is still not well defined. Quantitative and qualitative descriptions of the accumulation and advancement of NFTs throughout the cerebrum from both in vitro pathologic staining and in vivo flortaucipir NFT PET imaging characterizes the propagation of NFTs by increasing local intensity and increasing spatial extent. Here we describe a local accumulation connected spread (LACS) model of NFT propagation which naturally encompasses the intensity-extent phenomenon through a reaction-diffusion equation wherein the molecular mechanisms leading to tau accumulation in neurons represents the reaction and the expansion of tau with increasing disease stage along connected white matter trajectories is considered as a diffusion process. We explored three objectives to better understand the utility of the LACS model in predicting future NFT burden as represented by flortaucipir PET. First, we examined confounding factors inherent to flortaucipir PET and their effects on flortaucipir quantitation. Second, we generated a whole brain connectome to model the diffusion process and related harmonics of the connectome to flortaucipir uptake to understand concordance between connectivity and NFT burden. Third, we estimated parameters for LACS using Bayesian inversion to incorporate the uncertainties inherent to flortaucipir quantitation and the LACS model itself and predicted future NFT burden in a clinical trial population. The application of LACS modeling may provide insight into the accumulation and propagation of NFTs as represented by flortaucipir (FTP) PET throughout the cerebrum as well as the development of novel, tailored endpoints for AD therapeutic trials.

Introduction: The search for a preventative HIV vaccine is ongoing after three decades of research. Contributions of non-human primate (NHP) models to this research are irrefutable, however interpreting data obtained for translation to humans has been problematic. As knowledge concerning NHP models has accumulated, their utility and value in assessing immunogenicity and efficacy of novel vaccines have become apparent. NHP models have become a critical component of vaccine design. Areas covered: Beginning with early vaccine studies, we trace the development and evolution of NHP models concurrent with changes in HIV vaccine concepts and in response to their ability to predict clinical trial efficacy. The value of NHP studies in guiding vaccine design is highlighted along with their importance in opening new areas of investigation and facilitating movement of promising approaches into the clinic. Expert commentary: Due to their close relatedness to humans, NHPs are an excellent choice for immunogenicity studies. The ability of NHP models to predict clinical efficacy has improved with the introduction of low-dose challenge viruses and recognition of confounding variables in study outcomes. Use of NHP models has opened new research areas with outstanding potential for generating vaccine efficacy against HIV and other infectious agents.

Background: Endometriosis is a painful disorder in women where endometrium-like tissue exists outside of the uterine cavity. Progress on new therapies for the disorder is dependent on physiologically relevant models. Menstruation and development of spontaneous endometriosis only occur in women and Old World nonhuman primates making nonhuman primates the most suitable animals for study. Herein we review the use of nonhuman primates for studies on endometriosis. Objective: To describe the use of nonhuman primates for studies on endometriosis. Methods: We reviewed the literature comparing the use of primate models. Results: In practice, three types of “primate” models exist; 1) studies on monkeys with spontaneous endometriosis; 2) induction of endometriosis in disease-free animals; and, 3) the engraftment of primate tissue into immunodeficient rodents. The absence of tests to identify animals with the wellcharacterized disease greatly limits the viability of studies on spontaneous endometriosis in nonhuman primates. Despite this limitation, studies of spontaneous endometriosis have elucidated risk factors associated with the etiology and pathobiology of the disease. Induced endometriosis in the baboon and macaque currently represents the prototypic and most promising primate model, producing lesions that are phenotypically similar to endometriosis in women, with a well-controlled onset, and predictable pathogenesis. The strength of using induced endometriosis models in nonhuman primates lies in the ability to document the early disease process and the exact age of lesions in the animals. However, nonhuman primates are expensive and in short supply. Xenografts of primate tissue in immunodeficient mice also allow the study of the early disease process but long-term studies are a compromise because of the immunodeficient nature of the host animals. Studies of endometriosis in rhesus and cynomolgus macaques provides an additional benefit as these are the preferred primate models for pharmacokinetic and pharmacodynamic studies in many research institutes and the pharmaceutical industry. Conclusion: Due to the physiological similarities among primates, preclinical studies of endometriosis diagnostics and therapeutics conducted in nonhuman primate models are well-positioned to lead to new clinical applications. Keywords: Nonhuman primate, animal model, induced endometriosis, baboon macaque, xenograft models, pharmacokinetic.

The cytoskeleton and neurofibrillary tangles in Alzheimer's disease

Voxel-based analysis of Alzheimer's disease PET imaging using a triplet of radiotracers: PIB, FDDNP, and FDG