Drug Discovery

Determine which existing drugs or novel chemical compounds most safely and effectively disrupt the Alzheimer’s pathology generated by the highest priority genes.

Elucidation of the mechanism of action of Gamma Secretase Modulators

Researchers: 
Funding year(s): 
2013
Funding to date: 
$150,000

This project focuses on ultimately defining the structure of a soluble gamma-secretase modulator (SGSM)-bound gamma-secretase enzyme complex at high resolution. Defining the structure of this complex will provide critical information towards elucidating the mechanism of action of this promising series of therapeutic molecules known as SGSMs. This structural information will enable molecular dynamics simulations and can be used to identify critical sites of interaction between the SGSMs and their molecular target which we have shown to involve the catalytic subunit of the gamma-secretase enzymatic complex. These studies should enable a critical understanding of the mechanism of how these molecules selectively attenuate only the most pathogenic of the Abeta peptides, e.g., Abeta42 and could pave the way for identifying perhaps even more potent and more selective therapeutic agents for the treatment of Alzheimer’s disease.

Roadmap: 

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

Funding year(s): 
2013
Funding to date: 
$100,000

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. We refer to the occurrence of AD in people with DS by using the term DS/AD. Mouse genetic models of DS carry an extra copy of genes homologous to those on human chromosome 21. One of the best current genetic models of DS, Ts65Dn mice, exhibit abnormalities in brain structure and cognition similar to those observed in DS people, including the degeneration of specific neuronal populations, an effect shown to be caused by
increased gene dose for APP.

Monoacylglycerol lipase (MAGL) is an enzyme that belongs to the serine hydrolase family. It was shown that a selective antagonist of MAGL, JZL184, restored to normal the levels of pro‐inflammatory eicosanoids and inflammatory cytokines in a mouse model of AD (Piro et al., 2012); inactivation of MAGL also robustly suppressed production and accumulation of β‐amyloid (Aβ), a peptide product of APP, and improved synaptic plasticity and memory (Chen et al., 2012).

Therapeutic Hypothesis: That inhibiting MAGL will reduce AD related neuropathology, restoring to normal measures of inflammation, APP processing, synaptic plasticity and cognition.

The goal of this proposal is to validate monoacylglycerol lipase as a therapeutic target for ameliorating AD‐type neuropathology in DS, and by extension AD, thereby providing a novel approach to the treatment of these disorders.

Roadmap: 

Normalizing Abeta synaptic depression with drugs targeting PICK1

Funding year(s): 
2013
Funding to date: 
$100,000

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. We will test drugs that inhibit the interaction between synaptic receptors and PICK1; such drugs should act to normalize synaptic strength in the presence of elevated Aβ. These drugs may be lead compounds in the search for drugs to treat Alzheimer’s disease.

Roadmap: 

The Development of UDP Analogs for the Treatment of Alzheimer's Disease

Researchers: 
Funding year(s): 
2012
Funding to date: 
$100,000

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.

The brain is composed of two classes of cells, electrically active neurons and electrically silent glia. Over the past 20 years, Dr. Philip Haydon’s lab has focused its research efforts on understanding the role of glia in brain function. As a consequence, the scientists made a breakthrough discovery that these often-neglected cells offer new therapeutic opportunities for the treatment of disorders of the brain. In particular, they demonstrated that the activation of a glial receptor leads to the clearance of amyloid plaques and restores learning and memory in Alzheimer’s mouse models.

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 these glial receptors. The most efficacious molecules then will be tested for their ability to reverse plaque burden in mouse models of Alzheimer’s disease. Success in this project will allow Dr. Haydon and associates to leverage private and federal funds to develop a small biotech spin-off focused on glial cells, and will prepare this study for IND-enabling studies as well as Phase I clinical trials of compounds developed in this project.

Roadmap: 

Novel Soluble Gamma-Secretase Modulators for the Treatment of Alzheimer’s Disease Identification of the Molecular Target of Potent Gamma-Secretase Modulators

Researchers: 
Funding year(s): 
2011 to 2012
Funding to date: 
$300,000

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).

Dr. Steven Wagner and his fellow researchers recently discovered two structurally related series of gamma-secretase modulators (AGSMs and SGSMs) with potencies more than a thousandfold superior to tarenflurbil and many of the NSAID-like carboxylic acid-containing GSMs. The first series of these aryl 2-aminothiazole GSMs (AGSMs) are small molecules that bind directly to gamma-secretase, decreasing Abeta42 and Abeta40 levels while concomitantly increasing Abeta38 and Abeta37 levels without affecting gamma-secretase-mediated enzymatic processing of other known substrates, such as Notch-1.

AGSMs were shown to be efficacious in vivo for lowering the levels of Abeta42 and Abeta40 in both the plasma and brain of APP transgenic mice. Chronic efficacy studies revealed that one AGSM (compound 4) dramatically attenuated AD-like pathology in the Tg2576 APP transgenic mouse model. In addition, unlike the GSls, the AGSMs, by virtue of the fact they do not inhibit gamma-secretase, do not show Notch-related side effects that invariably appear in rodents and mice when treated chronically with GSls (e.g., no evidence of intestinal goblet cell hyperplasia). However, the very poor aqueous solubility of these AGSMs (<0.1 micromolar at neutral pH) may significantly compromise their further preclinical development due to the difficulties in achieving the escalated supraefficacious exposures necessary for safety and toxicity studies required for advanced preclinical development with such poorly soluble compounds.

More recently, the researchers discovered a second series of highly potent GSMs that have significantly improved physicochemical properties (e.g., aqueous solubilities at neutral pH) compared to the previously described AGSM series. These two structurally related series, as may be expected, behave similarly with respect to their effects on APP processing in steady- state cell-based assays. Both GSM series are able to lower Abeta42 and Abeta40 production while concomitantly increasing Abeta38 production without measurably affecting gamma-secretase- mediated processing of another known gamma-secretase substrate, namely, the Notch 1 receptor.

Roadmap: 

Molecular Tweezers—Novel Inhibitors of Amyloidogenic Proteins and Promising Drug Candidates for Alzheimer’s Disease

Researchers: 
Funding year(s): 
2011
Funding to date: 
$100,000

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.

This project addresses Alzheimer’s disease (AD) in the larger context of diseases caused by aberrant protein folding and self-assembly, which leads to formation of toxic oligomers and aggregates. In the last several years, Dr. Gal Bitan’s lab has been studying novel compounds called “molecular tweezers,” which modulate the aberrant assembly process using a previously unexplored “process-specific” mechanism. Their current lead compound effectively prevents formation of toxic aggregates of several disease-related proteins, including those involved in AD, Abeta and Tau. Initial in vivo experiments show peripheral administration of low doses of this compound lead to significant reduction of Abeta and Tau in the brain of transgenic mice.

In view of these promising data, they are poised to explore further the mechanism of action of the molecular tweezers and answer critical questions about their pharmacokinetics and safety.

Roadmap: 

ADAM10 and Dimebolin

Researchers: 
Funding year(s): 
2009
Funding to date: 
$150,000

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.

Roadmap: 

Core Facility for Abeta Microdialysis Drug Discovery Platform

Funding year(s): 
2007 to 2009
Funding to date: 
$278,238

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.

Roadmap: 

Novel Soluable Gamma-Secretase Modulators

Funding year(s): 
2010
Funding to date: 
$250,000

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.

Roadmap: 

Passive Tau Immunology

Funding year(s): 
2010 to 2011
Funding to date: 
$100,000

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.

Over the past year, we have firmly established a cell-based model of neurofibrillary tangle formation. NFTs in Alzheimer’s disease and related Tauopathies are comprised of insoluble hyperphosphorylated Tau protein, but the mechanisms underlying the conversion of highly soluble Tau into insoluble NFTs remain elusive. Dr. Lee has, with Cure Alzheimer’s Fund funding, conducted a series of experiments demonstrating that introducing minute quantities of misfolded preformed Tau fibrils (Tau pffs) into Tau-expressing cells will rapidly recruit large amounts of soluble Tau into filamentous inclusions (resembling NFTs) with unprecedented efficiency. This suggests a “seeding” recruitment process as a highly plausible mechanism underlying NFT formation in vivo. Consistent with the emerging concept of prion-like transmissibility of disease-causing amyloidogenic proteins, we found that spontaneous uptake of Tau pffs into cells is likely mediated by endocytosis, suggesting a potential mechanism for the propagation of Tau lesions.

Roadmap: