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Alzheimer's Disease Research - Vassilis Koliatsos, M.D.

Use of induced pluripotent stem cells (iPSCs) as humanized in vitro models for AD

With Dr. Vasiliki Mahairaki, Research Associate in the Division of Neuropathology, Dr. Koliatsos explores new opportunities afforded by iPSC technologies to
a) model important aspects of pathogenesis of familial AD (FAD) and
b) generate reagents in which mechanisms can be further explored and experimental therapeutics and diagnostics established.

In a just published paper (Mahairaki V et al, Stem Cells Dev, 2014), Drs. Koliatsos and Mahairaki with investigators in the Zambidis Lab at the Hopkins Institute of Cell Engineering established new lines of virus-free human iPSCs from patients with FAD harboring the disease-causing PSEN1mutation A246E that they differentiated to the neuronal lineage. They demonstrated that these human iPSC-derived neurons have mature phenotypic and physiological properties. They found that neurons from these iPSC lines express PSEN1-A246E mutations themselves and show AD-like biochemical features, that is, amyloidogenic processing of amyloid precursor protein (APP) indicated by an increase in β-amyloid (Aβ)42/Aβ40 ratio. Drs. Koliatsos and colleagues are very optimistic that familial AD-derived human iPSCs that harbor disease properties can be used as humanized models to test novel diagnostic methods and therapies and explore novel hypotheses for AD pathogenesis.

In another project that was recently funded by the Maryland Stem Cell Research Fund Drs. Mahairaki and Koliatsos are generating human neurons and astrocytes with amyloidogenic properties, i.e. neurons harboring PS1 mutations and astrocytes expressing ApoE4 alleles, and combine them in 3D co-culture systems to form extracellular Aβ deposits typical of AD. Building on established Aβ-generating interactions between neurons and glial cells, these co-culture systems are designed to enhance the amyloidogenic potential of their component parts. When grown in biocompatible hydrogel matrices, these systems reproduce the 3D complexity of the living nervous system and, in so far as they are based on human cells, they approximate human pathology. This work constitutes a pioneering effort to generate human cell-based models of Aβ amyloidogenesis in vitro. In view of several recent negative trials for AD, such models fulfill a critical need for simple assay systems in which large numbers of compounds such as β- and γ-secretase inhibitors and modulators or Aβ antibodies can be tested. We envision that the establishment and optimization of relatively simple in vitro systems will rekindle interest in research and development for new AD drugs that can halt the progression or prevent this devastating and increasingly prevalent disease in the future.

In another related study, Drs. Koliatsos and Mahairaki use their recently established lines of FAD-derived iPSCs to explore deficits in brain neurogenic niches as pathogenic mechanisms of FAD. Recent research indicates that some forms of AD may be associated with deficient neurogenesis, a problem suggesting that, in these cases, the ability of the brain to repair and maintain itself into advanced age is curtailed. Patient-derived iPSCs are ideally suited to address these problems in vitro and the use of the recently developed technique of cerebral organoids mimicking native brains can add substantially to these investigations. Drs. Koliatsos and Mahairaki explore the idea that the cell progeny of these iPSCs manifests common underlying problems at the neural precursor stage, including deficits in the self-maintenance of neural precursors and abnormalities in their efficient differentiation into neurons. They also explore the molecular mechanisms of these neurogenic deficits, for example deficiencies in Notch-1/CBF-1 signaling. This research contributes further to the idea that questions of pathogenesis or treatment of AD may be asked from patient-derived iPSCs differentiated into neural and neuronal or glial cells and used in a variety of humanized in vitro applications.

Animal models and clinical studies to explore the link between Traumatic Brain Injury and AD

Ongoing work in the Koliatsos Lab aims to better understand the links between repeat mild or moderate-severe TBI and AD. Recent work of Dr. Koliatsos with Dr. Xu, Research Associate in the Division of Neuropathology, has established and characterized animal models of repeat mild TBI. Using these models, Drs. Koliatsos and Xu have shown that repeat mild TBI causes diffuse axonal injury and accelerated tauopathy in genetically predisposed transgenic mice (P301S mice). With Drs. Xu and Ryu, Dr. Koliatsos currently extends this work to AppNL-F/NL-F knock-in mice harboring Swedish (NL) and Beyreuther/Iberian (F) mutations in the APP gene and ask the question whether repeat mild TBI also accelerates amyloidopathy. In parallel studies presently designed with Dr. Martin Pomper of the Department of Radiology and Dr. Hao-Yang Tan of the Lieber Institute Dr. Koliatsos is designing clinical multi-imaging studies (MRI, fMRI, and microglial, tau, and amyloid PET) that explore the predisposition to AD of 50+ year-old patients with history of moderate-severe TBI more than 10 years prior to enrollment.