Translational Research

Discover what the previously known Alzheimer’s genes can teach us about Alzheimer’s disease pathology and identify the role of the newly identified genes.

Generation of Neural Progenitor Cells Overexpressing Alzheimer’s Disease Genes with Familial Mutations and Analysis of Pathological Changes of Alzheimer’s Cells in Vivo

Funding year(s): 
2014
Funding to date: 
$100,000

We seek to evaluate the impact of candidate AD drugs on Abeta and tau pathology in human cellular AD models. In collaboration with Dr. Tanzi’s laboratory (Massachusetts General Hospital), we will test the impact of select candidate AD drugs on both Abeta and tau pathology in the 30 human neural cell culture models developed in Aim 4. In the first year, we found that SGSM41i, a candidate AD drug designed to specifically decrease the toxic Abeta42 generation, decreases not only the Abeta plaques but also the tau pathology in the 30 human cellular AD models. In the second year, we will test additional anti-Abeta drugs, including SGSM36, SGSM46 and SGSM49, which showed the higher potency in decreasing toxic Abeta species in vitro. We will test additional candidate AD drugs designed to block Abeta or Abeta-induced neuronal toxicity in the 30 human neural cell culture models. The overarching goal of this aim is to set up a unified platform that can be used for both studying the pathogenic mechanism of AD and evaluating target-based candidate AD drugs before human clinical trials.

Identification of Functional Properties of Human Alzheimer’s Disease Cells That Affect Their Bilateral Interactions with Brain Environment

Funding year(s): 
2014
Funding to date: 
$100,000

We will complete the characterization of the protective effects of neural progenitor cell (NPC) transplantation in E200K mice. We will also examine the effect of NPC transplantation on the progression of AD in 5xFAD mice, and we will characterize various pathological features of disease, rate of neurodegeneration and behavioral tests. These experiments may show for the first time whether it is possible to slow down neurodegeneration, particularly in models that are relevant to human AD. To compare the functional properties of NPSs from wild type vs. 5xFAD mice in vivo and in vitro, we will examine the response of resident adult NPCs to injury in vivo and compare that of 5xFAD to wild type mice. We will also compare the immune-modulatory and neuro-trophic properties of NPCs from 5xFAD and wild-type mice both in vitro (by co-culture and gene expression assays) and in vivo (by their effect of neurogenesis). These experiments will indicate whether NPCs from AD mice display defective functional properties. Finally, we will study the therapeutic functions of NPCs from human familial AD backgrounds compared with normal NPCs (to be provided by Dr. Noggle). We will examine human NPC properties using both in vitro and in vivo assays, as described above.

G2T Research Models and Materials

Researchers: 
Funding year(s): 
2014
Funding to date: 
$310,000
Taconic Biosciences GMBH, a global provider of genetically modified mouse models and associated services, is providing customized mouse models (transgenic, conventional/conditional knock out, conventional/conditional knock in) for each specific gene and type of mutation that will be studied in the Genes to Therapies™ project.

G2T Research Operations Management

Researchers: 
Funding year(s): 
2014
Funding to date: 
$135,650
As research operations manager for the Genes to Therapies™ (G2T) project, Wilma Wasco, Ph.D. will be responsible for facilitating communication among the various researchers, and managing and maintaining the core facilities and research materials, including specially engineered laboratory mice. She also will develop and maintain a G2T publications resource and provide the operations management necessary for this complex and unique undertaking.

The Role of TREML2 in Alzheimer's Disease

Researchers: 
Funding year(s): 
2014
Funding to date: 
$100,000

Recent genetic studies have demonstrated that a nonsynonimous polymorphism of the cell surface receptor TREM-Like 2 (TREML2) is protective for Alzheimer's disease (AD)1, 2. However, the function of TREML2 and its relationship to AD remain largely unresolved. Studies proposed in this application will provide the initial characterization of the expression and function of TREML2 in the human brain in AD and normal aging. Moreover, we propose the generation and the initial characterization of Treml2–/– mice, which will provide an invaluable resource for us and other investigators in the field for future mechanistic studies. This project will provide neurologists and immunologists with valuable resources that may be crucial for understanding the pathogenesis of AD and harnessing TREML2 for new strategies of therapeutic intervention in AD.

Generation of iPS Cells and Neurons from Skin Fibroblasts from Subjects with Familial and Sporadic AD

Funding year(s): 
2014
Funding to date: 
$200,000

Molecular, Biochemical and Functional Characterization of the AD iPS Cell Lines

Identification of Transcriptional and Proteomic Profiles of Familial and Sporadic AD iPS Cells

 
Genetic approaches have provided major insights into the molecular pathogenesis of AD. However, only about 3 percent of all of AD is due to genetic mutations in either amyloid precursor protein (APP) or presenilin 1 or 2 (PSEN1, PSEN2). A particular promise for the recent success in differentiating skin fibroblasts into phenotypes of brain neurons provides an unprecedented and unequaled cell system for exploring AD pathogenesis in both familial and sporadic AD. We propose to generate a human in vitro model using iPS cells, in which the genetic and developmental aspects of familial and sporadic AD can be studied more accurately and therapeutic targets can be identified for subsequent drug discovery. The cell-type specificity of key AD risk molecules (e.g., apoE and astrocytes) dictates that the complete modeling of the AD brain in culture will require the generation of neurons and glia and the study of these cells in mixed cultures. Ultimately, we will transplant these neurons into mouse brains in order to study their molecular and physiological properties in vivo.
 

Air Pollution and APP processing

Researchers: 
Funding year(s): 
2014
Funding to date: 
$90,908

We propose that urban traffic-derived nano-sized particulate matter (nPM, <0.1 um) in urban air pollution is a risk factor in AD by promoting amyloidogenesis. These experiments examine nPM induced ROS and pro-amyloidogenic APP processing.                

In the search for environmental factors in AD risk and progression, more than five epidemiological studies have associated premature cognitive declines with air pollutants. Correspondingly, rodent models in ours and two other labs show increased Aβ in response to selected air pollutants. Because nPM increases ROS and Aβ, and because H2O2 can induce Aβ production, we will evaluate the relationships of Abeta and to oxidative stress in responses to nPM. We focus on the olfactory neuroepithelium (O-NE), the initial neuronal contact with air pollutants, and the olfactory bulb (OB) which receives O-NE projections. In vivo, mice are given time-and dose controlled exposure to nPM, followed by analysis of O-NE and OB. In vitro, the O-NE will be exposed to nPM, in comparison with N2a cells carrying the swe-APP mutation which respond to nPM with increased Aβ. We also examine the potential of mitochondrial catalase (mCAT) for attenuating nPM induced Aβ and ROS. 

FX11 System’s Effect on Alzheimer’s Disease

Researchers: 
Funding year(s): 
2014
Funding to date: 
$100,000
Alzheimer’s disease (AD) results in neuronal death in the brain leading to cognitive problems. The disease is complex and in most cases is thought to have multiple contributing factors. Two systems that have been implicated in AD are blood coagulation and inflammation, since many AD patients have increased blockage of small cerebral blood vessels and increased brain inflammation. In this regard, one arm of the blood coagulation system can promote both the formation of blood clots and the initiation of inflammatory processes. This arm is initiated by activation of the blood protein Factor XII (FXII).
 
We and others have found that beta-amyloid (Aβ), a small peptide important for the development of AD, can activate FXII. This activation could lead to coagulation and inflammation, both of which could contribute to the subsequent death of brain cells. In fact, we have found that AD patients have more FXII activation in their blood than age-matched, non-demented controls.
 
These results suggest that the FXII system could be a significant factor in some cases of AD. We will investigate this possibility by studying mouse models of AD in which we can analyze and manipulate FXII and determine the effects on disease progression. If FXII contributes to the pathology of AD, it would open up new strategies for treatment of the disease.

Myeloperoxidase, Imaging and Treatment Target for Alzheimer’s Disease

Researchers: 
Funding year(s): 
2014
Funding to date: 
$100,000
Alzheimer’s disease (AD) is a challenging disease to diagnose and treat. Recent studies have shown that
innate immunity and inflammation play key roles in the pathogenesis of AD. Myeloperoxidase (MPO) is
a highly damaging substance secreted abundantly in inflammatory conditions by activated microglia and
astrocytes. MPO has been associated with beta-amyloid in both AD and animal models. MPO is more
abundant in female AD patients and those showing cognitive decline, and is also strongly implicated in
cardiovascular diseases, which can exacerbate AD. Our preliminary data showed that MPO activity can be
inhibited in animals and doing so improved outcome in murine models of neuroinflammatory diseases
and AD. As MPO is a key modulator of inflammation, and neuroinflammation is intimately associated
with beta-amyloid in animal models of AD and in human AD, the proposed project aims to establish MPO
as a biomarker for early neuroinflammation and damage, and MPO inhibition as a new therapeutic
strategy to decrease damage in AD. Given that neuroinflammation is an early event, MPO inhibition
could also be useful for early intervention to prevent progression of disease at the first signs of cognitive
decline prior to the onset of dementia in at-risk patients. Another key aspect of this proposal is the use of
novel multimodal in vivo molecular imaging technologies to monitor the status of both MPO and betaamyloid
noninvasively and longitudinally to assess treatment efficacy.

Alzheimer’s disease-associated mutations in PKCα: analysis of aberrant signaling output

Funding year(s): 
2014
Funding to date: 
$100,000
The goal of this project is to analyze how Alzheimers Disease (AD)-associated mutations in a key signaling molecule, protein kinase C α (PKCα), alter its function. PKCα plays a pivotal role in tuning the signaling output of cells and, as such, is frequently mutated in human cancers. The Alzheimer’s Genome Project led by Tanzi and colleagues has identified unique mutations in PKCα that co-segregate with AD in families with the disease. Our mechanistic insight into PKC structure and function sets the foundation for understanding how these mutations alter the function of the enzyme to contribute to the pathogenesis of AD.