Funded Research

Unique Research Funding Strategy

Cure Alzheimer’s Fund (CAF) takes a venture capital approach to medical research by finding the visionaries in the field, supporting them, focusing on the essentials by establishing a frugal culture and daring to be great. Our research objective is to support the scientists doing the most innovative work that will move knowledge of Alzheimer’s pathology most expeditiously to prevention and cure.

Our research follows a Research Roadmap designed by leading Alzheimer’s researchers who form the CAF Research Consortium. Proposals typically arise from members of the Consortium for their own work or complementary projects with or by others. Proposals are brief, with an emphasis on objectives, proposed outcomes, method and supporting data. They are reviewed by the chair of our Research Consortium and then by members of the Scientific Advisory Board. No scoring rubric is used; rather, questions or concerns are related to the researcher, who then may modify or explain the proposal accordingly. Mid-year and final reports are required. With sufficient reason to continue, some projects may be funded beyond one year. We do not accept unsolicited proposals, nor do we fund indirect costs or overhead at host institutions. Approval usually takes about two weeks, with funds delivered to the host institution within three weeks.

Project Description Researchers Funding
Alzheimer’s Genome Project™

The goal of this project is to evaluate our new Alzheimer’s disease gene candidates for effects on Alzheimer’s pathology and related biological pathways, including APP processing, amyloid beta protein generation, tangle formation and cell death. These studies are being carried out as part of Phase II of the Alzheimer’s Genome Project (AGP) and entail functional analyses of the Alzheimer’s gene candidates identified in Phase I of the AGP.

2005 to 2014
$10,641,400
Whole Genome Sequencing

We will carry out Whole Genome Sequencing (WGS) of all subjects in the National Institute of Mental Health (NIMH) Alzheimer’s disease family sample (1,510 subjects; 437 AD families). We will identify functional DNA variants throughout the human genome that are inherited as risk factors for Alzheimer’s disease. We also will analyze DNA from brain samples of subjects who exhibited significant Alzheimer’s pathology at autopsy, but never suffered from dementia; this will allow us to identify protective gene variants as well.

2012 to 2014
$3,000,000
The Amylin Protein of Diabetes Mellitus is an Antimicrobial Peptide

The goal of this project is to determine whether the amylin (IAPP) protein has a role in innate immunity (similar to Abeta) in order to significantly advance our understanding of the origins of diabetes pathology and its possible linkage to Alzheimer’s disease.

2010 to 2014
$1,600,000
The role of PICALM in vascular clearance of amyloid-B and neuronal injury

PICALM, the gene encoding phosphatidylinositol binding clathrin assembly (PICALM) protein, plays a key role in endocytosis, a process which regulates the function of cell receptors and synaptic transmission. Several GWAS studies of AD have replicated the association of PICALM with AD and shown relationships with neurodegenerative processes underlying disease. Additionally, low levels of PICALM in brain and cerebral microvessels have been recently shown in late onset AD. The role of PICALM in AD pathogenesis remains, however, elusive.

2014
$250,000
Orbitrap Fusion Tribid Mass Sprectrometer
The proposed grant will assist in the purchase of an Orbitrap Fusion Tribrid Mass Spectrometer system to
enable the development of a method to assess tau production and clearance rates in humans, animal models,
and in vitro experiments. This cutting edge mass spectrometer system will provide more precise measurements
with the ultra-low abundance of biomolecules of interest than current instruments can quantify. This will allow for
2014
$200,000
Regulation of tau oligomerization by interaction with TIA-­‐1, a component of stress granules

Published work from multiple groups indicates that tau phosphorylation causes tau to mis-­‐localize to the soma and dendrites, where TIA-­‐1 is present [20][21][22]. Our preliminary   data   indicates   that   the   TIA-­‐1   binds   the phosphorylated tau. Tau promotes formation of TIA-­‐1 based SGs, and in the process, binding of Tau with TIA-­‐1 stimulates tau misfolding.

2014
$100,000
Myeloperoxidase, imaging and treatment target for Alzheimer’s Disease
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
2014
$100,000
Characterizing the role of LOAD-associated variants of DLGAP1 in AD

There is general agreement that beta amyloid (Aβ) is a likely causative agent in the development of Alzheimer’s disease. There is growing evidence that early in the disease an important target of Aβ is the synapse, the site of communication between neurons. We have found that exposure of synapses to Aβ causes synaptic loss. In this proposal we will examine the role played in this process by variant forms of synaptic proteins that have recently been identified by Dr. Tanzi in whole genome analysis of families with late-onset Alzheimer’s disease (LOAD).

2014
$100,000
Patient-derived Reprogrammed Neurons as a Model to Study Neurodegenerative Diseases in a Dish

Alzheimer's disease is the most common form of dementia, affecting over 5 million people in the United States alone; it is the sixth-leading cause of death and is expected to cost the nation over $200 billion in 2013, with costs projected to exceed $1 trillion by 2050. Currently, there is no cure for Alzheimer's disease, nor are there effective treatments that delay or improve symptoms.

2014
$100,000
FX11 system’s effect on AD
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.
2014
$100,000
Alzheimer’s disease-associated mutations in PKCα: analysis of aberrant signaling output
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.
2014
$100,000
GABAergic inhibitory efficiency and adult neurogenesis in the hippocampus of aged Ts65Dn mice, a model of ‘Alzheimer’s disease in Down syndrome’, after chronic treatment with the monoacylglycerol lipase inhibitor JZL184

Recently we observed that chronic suppression of monoacylglycerol lipase with the selective blocker JZL184 increased brain levels of endocannabinoid 2-arachidonoil glycerol (2-AG), restored long-term potentiation, improved cognition, and reduced brain levels of Aβ40 and Aβ42 in aged Ts65Dn mice, a model of ‘Alzheimer’s disease in Down syndrome’ (ADDS). In this proposal, we plan to examine the mechanisms responsible for the restoration of cognition and synaptic plasticity in the ADDS model mice.

2014
$100,000
Molecular mechanisms of synaptic plasticity in the hippocampus: A path to novel therapies

There is strong evidence suggesting that Alzheimer’s disease is caused in large part by the accumulation of a toxic protein termed A-beta (Aβ) in the brain. If scientists can understand in great molecular detail the very early steps of how Aβ accumulation impairs brain function, it will be possible to develop therapies that prevent these steps.  One of the earliest effects of toxic forms of Aβ is to impair the ability of the connections between nerve cells, termed synapses, to modify their own properties in response to changes in the patterns of brain activity.

2014
$100,000
Air pollution and APP processing

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.                

2014
$90,908
High-Throughput Multiplex Real-Time PCR For CSF-Biomarker And MicroRNA Profiling In AD

This project will fund the purchase of a high-throughput real-time PCR instrument that will allow to us to achieve two scientific goals:

i) expand the ongoing projects on AD biomarker genetics to a large, newly recruited cohort of dementia patients and healthy controls for whom both CSF biomarker data (i.e. levels of Aβ, Aβ42, tau, phospho-tau proteins) and DNA samples are already available, and

2014
$72,355
Stem Cell Consortium

Stem cells are the least mature cells in the body. Because these cells are so immature, they can be treated with a defined cocktail of factors and, depending on which factors are used and in what sequence, those factors can cause maturation of cells along discrete cell types. With a new tool called induced pluripotent stem cells, it now is possible to take skin cells from adults and return them to this immature state. By redirecting skin cells from Alzheimer’s patients and turning them into nerve cells, we are able to study adult Alzheimer’s neurons (nerve cells) in the lab.

2013
$600,000
Upkeep and Maintenance of the AlzGene Database

Cure Alzheimer’s Fund is funding the upkeep and continued development of a revolutionary Web-based database. AlzGene is a fantastic resource for Alzheimer’s researchers, providing data and meta-analyses from hundreds of genetic association studies in an easy-to-use, searchable database. Scientists interested in a particular gene can search for it in AlzGene to see what previous studies have reported, receiving a wealth of information in a very short amount of time.

2006 to 2013
$389,172
Aβ Oligomers and the Pathogenic Spread of Tau Aggregation: Implications for Alzheimer’s Disease Mechanism and Treatment

The goal of this project is to conduct a series of experiments designed to elucidate the role of Abeta and exosomes (vesicles involved in “cell-to-cell signaling”) in the transfer of Tau clumps from nerve cell to nerve cell.

2012 to 2013
$251,000
The roles of Eps homology domain (EHD) proteins and synaptic activity in axon transport of the Alzheimer’s β-secretase BACE1 in the brain

The membrane-bound aspartic protease 13-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the 13-secretase enzyme that generates the first cleavage in the formation of the 13-amyloid (AI3) peptide from APP (1). Thus, BACE1 is a prime therapeutic target for Alzheimer's disease (AD). However, BACE1 inhibitors with drug-like properties that cross the blood-brain barrier (BBB) have proven difficult to develop.

2012 to 2013
$200,000
BACE1 transcytosis in Alzheimer’s disease pathogenesis

Many lines of evidence suggest that beta-amyloid peptides cause neuronal damage and affect fundamental memory processes early in the course of Alzheimer's disease (AD). Two membrane-associated enzymes, namely betasecretase (BACEl) and gamma-secretase are responsible for beta-amyloid production. Understanding the details regarding the cellular and molecular mechanisms involved in beta-amyloid production in neurons is a topic of central importance in molecular AD research.

2012 to 2013
$200,000
Elucidation of the mechanism of action of Gamma Secretase Modulators

This project focuses on ultimately defining the structure of a soluble gamma-secretase modulator (SGSM)-bound gamma-secretase enzyme complex at high resolution.

2013
$150,000
Sleep and tauopathies: Effect of an anti-tau antibody

In neurodegenerative diseases known as the tauopathies (e.g. progressive supranuclear palsy, Alzheimer disease), there is progressive degeneration of specific brain regions that account for the symptoms and signs of each disease.  Accumulation of aggregated forms of the protein tau in structures known as neurofibrillary tangles and dystrophic neurites in these brain regions correlates well with functional decline in cognition, motor, and other functions.

2013
$100,000
Discovery of Alzheimer’s Disease Blood Biomarkers Using Phage Display Technology

Absence of biomarkers has posed a formidable challenge in the development of effective treatment for Alzheimer disease (AD). Blood-based biomarkers could offer advantages that allow for early AD diagnosis and are critical in monitoring efficacy in clinical studies. Proposed studies aim to identify a set of novel blood biomarkers and examine their potential application as diagnostic agents. Phage display is a powerful approach to engineer peptides or proteins for binding to targets of interest.

2013
$100,000
Characterization of the pathological significance of a novel type of vascular amyloid

The amyloid Aß peptide is deposited in at least two distinct locations in AD brain:  Parenchymal plaques and vascular amyloid deposits in the wall of arterioles, where it is associated with vascular smooth muscle cell degeneration and stroke (Congophilic amyloid angiopathy, CAA).  While CAA is commonly found in AD brain, some human mutations within the Aß domain of the amyloid precursor protein (APP) cause CAA and stroke, rather than AD indicating that these diseases can occur independently.

2013
$100,000
Effects of Inhibitors of Monoacylglycerol Lipase on Behavior and Synaptic Plasticity of Ts65Dn Mice, a Genetic Model of Down Syndrome

Alzheimer’s Disease (AD) is caused by a complex interplay between genetic, epigenetic and environmental factors. Mutations in three genes, amyloid precursor protein (APP), presenilin (PS)‐1 and (PS)‐2 account for early onset autosomal dominant AD (Bertram and Tanzi, 2012). People with Down syndrome (DS) carry and extra copy of chromosome 21, which contains a copy of the APP gene. As a result, by the 4th decade all people with DS exhibit the AD type neuropathology and most go on to show dementia by age 60. Thus, DS can be regarded as a valid and robust model of AD.

2013
$100,000
Vascular Regenerative Therapy for Alzheimer’s Disease

Alzheimer’s disease (AD) is a major cause of dementia in elderly. The amyloid-β (Aβ) peptides deposit in the brain parenchyma as senile plaques and in the cerebrovasculature as cerebral amyloid angiopathy (CAA), both are hallmarks of AD pathology. Epidemiologically, cerebrovascular damages caused by diabetes mellitus or stroke increase the risk for AD. Cerebral hypoperfusion precedes cognitive decline and neurodegeneration in AD. Our recent work has also demonstrated that cerebrovasculature plays critical roles in Aβ clearance.

2013
$100,000
Normalizing Abeta synaptic depression with drugs targeting PICK1

There is general agreement that beta amyloid (Aβ) is a likely causative agent in the development of Alzheimer’s disease. There is growing evidence that early in the disease an important target of Aβ is the synapse, the site of communication between neurons. We have found that exposure of synapses to Aβ causes their weakening. In this proposal we will examine the role played by PICK1, a protein that associates with synaptic receptors and participates in the weakening of synapses by Aβ.

2013
$100,000
The Root of Alzheimer’s Disease: Purification and Characterization of Amyloid-beta Oligomers from the Human Brain

Large, poorly soluble aggregates of the amyloid-beta peptide form the senile plaques that are a pathological hallmark of Alzheimer’s disease, but the extent of plaque deposition correlates only moderately with dementia; for example many middle aged and elderly people have extensive plaque deposition without any signs of dementia. Instead, several types of smaller water soluble amyloid-beta oligomers have been found to be more toxic than either plaques or amyloid-beta peptide monomers.

2013
$100,000
Novel Soluble Gamma-Secretase Modulators for the Treatment of Alzheimer’s Disease Identification of the Molecular Target of Potent Gamma-Secretase Modulators

The goal of this project is to identify a series of highly potent gamma-secretase modulators able to lower Abeta42 and Abeta40 production while concomitantly increasing the less toxic production of Abeta38 without measurably affecting gamma-secretase-mediated processing of the Notch 1 receptor (which is very important in a variety of cellular processes for cell-to-cell communication).

2011 to 2012
$300,000
Antibody Signature of Alzheimer’s Disease: Promise of an Early Diagnostic Test

A physician can’t cure what he can’t diagnose. The diagnosis of Alzheimer's disease is based on the exclusion of several neurological syndromes, rather than directly testing for the disease of interest. This can be an inaccurate exercise in up to 20% of the cases. Promising biomarkers are being developed, such as the cerebrospinal fluid profile of beta amyloid and tau proteins, as well as amyloid imaging with positron-emission tomography.

2012
$100,000
Brain Structure, Abeta Metabolism and Behavior in Mice Deficient in Diabetes and Alzheimer's Associated SorCS1

This is an extension of an earlier grant. SorCS1 and SorL1/SorLA/LR11 belong to the sortilin family of vacuolar protein sorting-10 (Vps10) domain-containing proteins. Both are genetically associated with Alzheimer’s disease (AD), and SORL1 expression is decreased in the brains of patients suffering from AD. SorCS1 also is associated genetically with Types 1 and 2 diabetes mellitus (T1DM, T2DM).

2010 to 2012
$100,000
The Putative Role of Red Blood Cell CR1 levels in Amyloid Beta Clearance and Alzheimer’s Disease Pathogenesis.

The immune system uses complement proteins and receptors to “coat and clear” pathogens and proteins from the body. Complement Receptor 1 (CR1/CD35) is found on the surface of red blood cells in humans and helps shuttle cellular debris to the liver for degradation. Recently, specific genetic variations, called polymorphisms, in the CR1 gene were found to be associated with an increased risk of late-onset Alzheimer’s disease.

2012
$100,000
General Anesthetics and Alzheimer’s Disease

The goal of this project is to test the hypothesis that desflurane is a safer anesthetic than isoflurane for AD patients in order to find safer anesthetics that won’t worsen AD symptoms.

2012
$100,000
The Development of UDP Analogs for the Treatment of Alzheimer's Disease

The goal of this project is to collaborate with a medicinal chemist to design, synthesize and test the efficacy of third-generation small molecules that will activate glial receptors. The most efficacious molecules then will be tested for their ability to reverse plaque burden in mouse models of Alzheimer’s disease.

2012
$100,000
iPS-derived and trans-differentiated human neurons as models to study Alzheimer’s disease

Recent groundbreaking work in stem cell biology has made it possible to reprogram non-neuronal cells obtained from Alzheimer’s diseased patients into neurons. For the first time, the research community has the means to study diseased human neurons from Alzheimer’s patients. These models have already yielded novel insights into the disease.

2012
$100,000
The role of PICALM in vascular clearance of amyloid-β

PICALM, the gene encoding phosphatidylinositol binding clathrin assembly (picalm) protein, plays a key role in endocytosis, a process which regulates the function of cell receptors and synaptic transmission. PICALM is one of the most highly validated Alzheimer’s disease (AD) risk factors. Its role in AD, however, is unknown. A recent genome-wide screen for modifiers of amyloid-b peptide (Aβ) toxicity in yeast has identified the key role of the yeast homologue of PICALM.

2012
$100,000
Investigations of the Mechanism of Action of TagretinR/Bexarotene on Amyloid Clearance in Transgenic Mouse Models

Recent studies from the laboratory of Dr. Gary Landreth (Cramer P. et. al (2012) Science 335) have demonstrated that Bexarotene (Targretin), a highly selective, blood-brain barrier-permeant, FDA-approved, RXR agonist for the treatment of cutaneous T-cell lymphoma, can rapidly reduce amyloid plaque burden and rescue behavioral deficits in transgenic mouse models of AD. The proposed mechanism of action is via transcriptional activation of PPARγ:RXR- and LXR:RXR-regulated genes, including ApoE, ABCA1 and ABCG1 expression, that facilitates Aβ clearance and promotes microglial phagocytosis.

2012
$50,343
Optimization of Novel ACAT Inhibitors for Alzheimer's Disease

The goal of this project is to test three novel ACAT inhibitors to determine whether they will prevent development of amyloid pathology and alter APP processing in AD mice in order to prevent and treat AD.

2011
$150,000
Understand the Role of ADAM10 in the Pathogenesis of Alzheimer's Disease After Head Trauma

The goal of this project is to determine whether increased sAPPα levels are capable of reducing the production of neurotoxic Abeta following head trauma in order to reduce the risk of developing Alzheimer’s disease following brain injury.

2011
$100,000
Metallomic Mapping of the Aging Brain in Trg2576 Transgenic Mouse Model

The goal of this project is to perform the first high-resolution metallomic brain maps of key biometals (copper, zinc, iron) during normal brain aging and in Alzheimer’s disease in order to develop disease-modifying treatments that target normalization of biometal distribution and metal-protein interactions in the brain.

2011
$100,000
Selective Cell Vulnerability in Alzheimer's Disease

The goal of this project is to identify cells that are both most vulnerable and most resistant to Alzheimer’s disease in order to develop drugs that will protect the most vulnerable.

2011
$100,000
Understanding the Up-Regulation of Neuroserpin in the Alzheimer’s Brain and Isolating a Potential Therapeutic Inhibitor of its Action: Continued

The goal of this project is to determine if there is a strong correlation between Alzheimer’s patients with high neuroserpin and high thyroid hormone levels (for both males and females).

Since our initial proposal in Spring 2010, several papers have appeared making the association between thyroid hormone levels and dementia. Thyroid hormones are associated with poorer cognition in mild cognitive impairment. (Dementia Geriatrics & Cognitive Disorders 30:205-11. Bensenor, IM et al. 2010, Subclinical hyperthyroidism and dementia. BMC Public Health 10:298.)

2010 to 2011
$100,000
Effect of Bexarotene on Abeta in APP Tg Mice Expressing ApoE3 and ApoE4

The goal of this project is to determine the effects of bexarotene on both Abeta and ApoE metabolism in the presence of human Abeta and human ApoE isoforms (any of two or more functionally similar proteins that have a similar but different amino acid sequence) because it is relevant to potential effects of similar drugs in humans.

2011
$100,000
Molecular Tweezers—Novel Inhibitors of Amyloidogenic Proteins and Promising Drug Candidates for Alzheimer’s Disease

The goal of this project is to plan expanded in vivo characterization of the efficacy of “molecular tweezers” toward development of disease-modifying therapy for AD and related diseases.

2011
$100,000
Passive Tau Immunology

Neurofibrillary tangles (NFTs) are biomarkers for Alzheimer’s disease and are the products of a breakdown in part of the structure of cells (Tau), leading to neural cell death. The goal of this project is to establish the first cellular system that develops authentic NFT-like Tau aggregates to provide mechanistic insights into NFT pathogenesis and a potential tool for identifying Tau- based therapeutics.

2010 to 2011
$100,000
Modulation of Abeta Deposition by Cell-Specific Mechanisms

The goal of this project is to determine which types of cells and factors in the brain influence excess Abeta deposition in Alzheimer’s patients, using animal models of the disease.

2010 to 2011
$100,000
Structural and Functional Analysis of Novel Abeta and Tau Oligomers Using Conformation-Specific Monoclonal Antibodies

The goal of this project is to determine which oligomers of Abeta and Tau are most damaging and whether specific antibodies can prevent formation of those oligomers.

2011
$100,000
Mechanisms of Retinoid X Receptor-Mediated Abeta Clearance in Alzheimers' Disease

The goal of this project is to investigate the mechanisms through which RXRs (retinoid x nuclear receptor) promote amyloid clearance from the brain.

2011
$100,000
Exploring Adult Neurogenesis as a Therapeutic Target for Alzheimer's Disease

The goal of this project is to test whether the strategy of stimulating endogenous stem cells in the AD brain is safe in order to find treatment for Alzheimer’s patients.

Recent evidence shows the adult brain contains discrete populations of stem cells that retain the capacity to generate new neurons through the process of neurogenesis. Dr. Se Hoon Choi will test whether the strategy of stimulating endogenous stem cells in the AD brain is safe and effective ultimately to find treatment for Alzheimer’s patients.

2011
$100,000
Cellular and Animal Models of Amyloid Pathology in Early Alzheimer's Disease

The goal of this project is to evaluate the pathological significance of a new type of Abeta deposits in the brain (at the onset of Alzheimer’s disease) in order to develop a novel mechanism for amyloid pathogenesis to help convince the FDA to approve and support early clinical trials.

2011
$100,000
Alzheimer Disease Models Based on Human Neural Progenitor Cells

The goal of this project is to develop genetically modified human neural progenitor cells that can replicate Alzheimer’s disease pathology in in vitro and in vivo conditions in order to develop and test Alzheimer disease drugs in human brain cells.

2011
$100,000
Curcumin Collaborative Project

This collaborative project will identify and characterize novel curcumin-like derivatives for the treatment and prevention of Alzheimer’s disease. The purpose of the study is to develop means of overcoming obstacles to rapid breakdown and creating methodologies for precisely delivering curcumin derivatives to appropriate locations within the brain.

2010
$400,000
Three Studies of ACAT Inhibitors as Potential Therapies for AD

It is known that high cholesterol is associated with cardiovascular disease. Cholesterol also regulates the production of the toxic amyloid beta (Aβ) peptide in Alzheimer’s disease (AD). Therapies already developed or in development for dyslipidemia and atherosclerosis are becoming attractive for reducing Aβ in the brains of patients affected by AD. We have previously reported that drugs specifically targeting one step of the cholesterol pathway, acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors, reduced generation of toxic Aβ peptide in cells and an animal model of AD.

2004 to 2010
$300,000
Novel Soluable Gamma-Secretase Modulators

Building on in vitro characterization of a novel series of soluable gamma-secretase modulators (SGSMs) funded by Cure Alzheimer’s Fund, the current project is a thorough pharmacological or in vivo examination of these molecules to identify the best or “lead” drug candidate.

2010
$250,000
NMDA Receptors

The traditional signaling induced by NMDA-Rs is triggered by the Ca2+ ions that pass through the NMDA-R channel. However, preliminary data indicate that blockers at the NR2B subunit, but not the NR1 subunit or the channel of the NMDA receptor, prevent the synaptic effects of the NMDA receptor. These findings suggest that Abeta employs novel, non-ion flux NMDA-R signaling mechanisms to produce synaptic depression. These results may open up a new group of potential therapeutic targets for treatment of Alzheimer’s disease.

2010
$100,000
Anti-APOE Antibodies

In this project, the researchers hypothesize that targeting apoE, a component of amyloid plaques, can result in less Aβ aggregation in the brain and decreased Aβ-related pathology and that this treatment will have fewer side effects than the use of anti-Aβ antibodies. The project will test this hypothesis in this proposal in the context of human apoE isoforms.

2010
$100,000
Mouse Model for Non-Generic Alzheimer's Disease

The SAMP8 mouse model line is a model of accelerated senescence, and interestingly, develops sparse amyloid plaques, which is remarkable given the less amyloidogeneic properties of murine Aß. Hence, the research hypothesis for this project is that by introducing the more amyloidogenic human APP at the endogenous locus, researchers will be able to more robustly mimic the onset of sporadic Alzheimer’s disease, and thereby utilize this model for pre-clinical development and for widespread distribution to other investigators in the field.

2010
$63,851
Peek and Treat Approach to Diagnosis, Treatment and Monitoring of AD

The objective of this project is to develop a nanotechnology platform that can simultaneously be used to diagnose and treat Alzheimer's. The work will explore how to develop multifunctional nanocarriers that contain both an imaging agent and a therpeutic agent and also will improve the binding capabilities of the nanocarrier allowing regulation of the release of therapeutic molecules to amyloid lesions.

2010
$40,000
Core Facility for Abeta Microdialysis Drug Discovery Platform

In collaboration with an anonymous funder, Cure Alzheimer’s Fund is supporting development of a facility to measure the concentration of Amyloid-beta in real time in the brain of living, behaving mouse models that develop features of AD. The model enables screening for drugs that lower Amyloid-beta directly in the brain in relatively high throughput.

2007 to 2009
$278,238
Potential for Host Cytotoxicity from Microbially-derived Abeta Oligomers

Alzheimer’s disease (AD) is the most common form of dementia in the elderly afflicting over 20 million people worldwide. Two decades of findings from cell biology, genetic, neuropathological, biochemical and animal studies overwhelmingly point to the β-amyloid peptide (Aβ) as the key protein in the disease’s pathology (see review by Hardy and Selkoe, 20001). Aβ appears to be a soluble component of normal brain. However, in AD brain the peptide accumulates as β-amyloid, an insoluble semi-crystalline deposit that is the hallmark of the disease pathology.

2009
$250,000
Design, Synthesis and Characterization of Novel and Potent Gamma Secretase Modulators: Physiochemical and Pharmacokinetic Properties

During the past year, our laboratory at UCSD (Wagner laboratory), in close collaboration with the Tanzi laboratory at MGH, discovered, synthesized and characterized (in vitro) a novel series of molecules able to potently prevent the formation of what is currently thought to be the pathogenic culprit of Alzheimer’s disease (AD).

2009
$200,000
ADAM10 and Dimebolin

Understanding the hypothesized relationship between ADAM10, a newly identified Alzheimer’s-related gene, and dimebolin, the key ingredient in the anti-Alzheimer’s drug Dimebon.

2009
$150,000
miRNAs in AD Pathology

This project will test the hypothesis that microRNAs regulate protein levels of APP and Genome Wide Association Screen (GWAS)-identified levels of APP and GWAS-identified risk genes.

2009
$100,000
Development of Tau Microdialysis as a Method to Study Tau Metabolism, Pathophysiology and Response to Treatment

The hypothesis of this proposal is that a method can be developed to measure tau levels in the extracellular space of the brain (interstitial fluid–ISF) and that assessment of ISF tau in both normal mice as well as a variety of animal models that develop AD pathology will provide new insights into tau metabolism and the relationship between Aβ and tau in AD. If this method development is successful, it has a chance to tell us more about the pathophysiology of AD as well as a provide a novel way to screen for new AD treatments.

2009
$100,000
Rescue of Synapses in AD Rodent Models

Excessive synaptic loss is thought to be one of the earliest events in Alzheimer’s disease (AD). In our previous studies, we have shown that amyloid beta (Aβ), a peptide implicated in the pathogenesis of AD, is secreted in an activity-modulated manner. Furthermore, we found that secreted Aβ leads to loss of synaptic receptors (by endocytosis), synaptic depression and removal of dendritic spines, sites of excitatory synaptic transmission.

2009
$100,000
Oligomer Collaborative Projects

A collaboration of members of the Research Consortium, a member of the Cure Alzheimer’s Fund Science Advisory Board and non-Cure Alzheimer’s Fund-affiliated researchers hypothesizes that an abnormal increase in levels of synaptic Abeta and, particularly, Abeta oligomers may lead to synaptic dysfunction, cognitive decline and eventually dementia. This highly innovative collaborative project will address how Abeta oligomers are formed and which types detrimentally impact synaptic dysfunction and neuronal survival in the brain.

2006 to 2008
$1,550,000
Investigation of Certain Properties of Mitochondria Membranes Related to AD

While the mechanism of Aβ cytotoxicity remains contentious, evidence is accumulating that membrane permiabilization plays a key role in the pathological activity of the peptide. This study will focus on role of Aβ oligomerization in the Aβ-mediated disruption of lipid bilayers.

2008
$200,000
Fine Mapping of Prioritized GWAS Results

In this application we propose to utilize next-generation sequencing combined with high-efficiency genomic sequence capture to systematically fine-map the 14q31 region which, based on the currently available data, very likely contains an important AD susceptibility locus(i). Newly identified variants will be followed up in more than 5,500 DNAs from both family-based and case-control backgrounds.

2008
$127,880
Molecular Mechanism Underlying Hippocampal Neurogenisis by Familial AD-linked Presenilin-1 Variants

The specific hypothesis behind the proposed research is that presenilin 1 regulates cell fate determination of adult neural progenitor cells by interfering with instructive intercellular signals prevailing within the neural progenitor cell niche, and that expression of the familial AD-linked presenilin 1adversely affects this process.

2008
$100,000
Defining the Effects of Physiological Synaptic Activity on Abeta Levels: Implications for AD

The objective of this proposal is to determine the effect of physiological alterations in neuronal activity on ISF Aβ levels in vivo. Such information may provide important information as to how to potentially regulate the probability of whether or not Aβ will or will not ultimately aggregate in the brain and initiate the process we know of as AD. We will utilize in vivo microdialysis with concurrent electrophysiological recordings to determine how physiological changes in neuronal activity dynamically affects ISF Aβ.

2008
$100,000
Modulation of Abeta Assembly and Cytotoxicity by a Fragment of Myelin Basic Protein

We have identified myelin basic protein (MBP) as a novel factor in brain that can bind Abeta and potently inhibit its assembly into fibrils. In light of this novel finding the overall hypothesis of this proposal is that defined fragments of MBP can regulate Abeta assembly and modulate its cytotoxic properties. This will provide the basis for developing novel and potent Abeta assembly inhibitors.

2008
$100,000
Understanding the Cell Biology Underlying the Effects of Abeta on Synapse

This research will attempt to understand the following central cell biological questions:

2008
$100,000
TBI and Stroke Relationship to Alzheimer’s Disease

Investigating the increasingly documented link between TBI/stroke and Alzheimer’s disease is aimed not only at developing effective interruptions of that linkage but also a contribution to an understanding of the basic Alzheimer’s disease mechanism.

2008
$50,000
Support of Central Spinal Fluid Biomarker Study–ADNI

Cure Alzheimer's Fund is part of a funding consortium supporting collaborative biomarker investigation of the elevation of tau and decreased concentrations of Amyloid beta 42 in the Central Spinal Fluid as evidence of the presence of the Alzheimer's disease pathology.

2008
Identification of Agents that Inhibit the Generation and Neurotoxicity of Cross-linked B-amyloid Protein Species

We have coined the term CAPS to describe cross-linked-Beta-amyloid protein species. CAPS, particularly dimeric forms, are highly neurotoxic. CAPS are also abundant in vivo, with dimeric species alone comprising as much as 40 percent of the total Abeta pool in late state AD brain. In this study we plan to screen compound libraries for potential therapeutic agents that attenuate the levels and/or cytotoxic activity of CAPS.

2006 to 2007
$200,000
Relating AD Brain Morphology to AD Genotype

The Massachusetts Alzheimer’s Disease Center has collected approximately 800 brain samples, providing an extraordinary resource for clinical-pathological correlations for Alzheimer’s disease and other dementias.

2006
$100,000
Longitudinal Study of AD Genotypes

This study draws on a unique community-based longitudinal cohort of 378 subjects who span the range of impairment between normal aging and mild Alzheimer's disease (AD). This research focuses on two key steps to find AD genes and to understand their impact.

2006
$100,000