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THE LANDRETH LAB

 

WELCOME TO THE LANDRETH LAB!

Some vital information about our recent discoveries...

Thank you!


Thank you for your interest in our work, we are touched you have reached out to the Alzheimer’s Research Laboratory. We are excited about our findings, and are hopeful that the work we have done in mice will translate to an effective treatment for those with Alzheimer's disease. It is very early in the process, and while we are not currently enrolling patients in clinical trials, it is probable that any subsequent clinical trial will be carried out through NIH-sponsored Alzheimer's Disease Research Centers. For those interested in clinical research today, our recommendation is to connect with the Alzheimer's Association website, as they have a program in place for connecting people with clinical trials. Here is the link:

Find Clinical Trials

Again, our best to you from everyone here at the Alzheimer's Lab at Case Western Reserve University School of Medicine

Requests for Clinical Trials

We have received hundreds of emails and phone calls about clinical trials. We are sorry that we are unable to respond individually to each query.

A phase I proof of mechanism trial will start soon to test the effect of the drug in the brains of normal subjects. We are not accepting additional subjects for this trial

We are currently determining how best to administer the drug and resolve several scientific issues. These studies will take some time and we are working as fast as our resources allow. These studies must be completed before we can design a Phase II trial. We do not know when we can begin these latter trials.

We STRONGLY DISCOURAGE any off label usage of bexarotene. There are potential serious adverse effects in individuals with diagnosed Alzheimer's disease.

This is all the information that is currently available. Any new developments will be posted here.


Information about the Landreth Lab...

The Landreth lab has two distinct areas of interest that are centered on understanding disorders of the nervous system.

Alzheimer’s Disease
Alzheimer's disease if the primary focus of work in the laboratory.

Microglial-mediated inflammation: Over the past 15 years the laboratory has investigated the roles of microglia and inflammation in AD pathogenesis. Microglia are the immune system’s representative in the brain. The development of fibrillar forms of amyloid and their deposition into plaques provokes the ‘activation’ of microglia, who ‘see’ these structures as foreign and mount an inflammatory response. The inflammatory mediators then elicit a broad array of effects in the AD brain which act to exacerbate the primary disease process and accelerate disease progression. We have investigated the cellular mechanisms through which the microglia are able to detect and respond to amyloid deposits. Current work is focused on understanding how to provoke the microglia to become ‘alternatively activated’, a state that is correlated with the resolution of inflammation and induction of tissue repair mechanisms, including the stimulation of phagocytosis. One of the enigmatic features of the disease is that microglia are competent phagocytes, but fail to effectively remove plaques from the brain. We are now investigating how to stimulate the phagocytic properties of these cells.

Why is ApoE a risk factor for AD? Apolipoprotein E is the principal apolipoprotein in the brain. ApoE acts to scaffold the formation of high density lipoprotein particles which are responsible for trafficking of cholesterol and phospholipids throughout the brain. In humans, allelic variation in the APOE gene results in expression of 3 different forms, ApoE2, E3 and E4. The APOE4 gene is associated with dramatically elevated risk for the disease. The ApoE4 gene product differs from others as it only supports the formation of smaller, less stable HDL particles. Our contribution to this discussion arose from the observation that ApoE-based HDLs act physiologically to promote the proteolytic clearance of Aß from the brain. Importantly, ApoE4 is impaired in this function and we argue that this may be the basis of its association with increased disease risk. We are now investigating the mechanisms through which ApoE facilitates Aß degradation.

New therapeutics: A primary goal of the work in the lab is to develop new therapeutic approaches to AD. We have investigated the actions of nuclear receptors on regulating ApoE metabolism and inflammation. Nuclear receptors are ligand-activated transcription factors that control many aspects of metabolism. We have found that agonists of peroxisome proliferator-activated receptor gamma (PPARγ) and liver X receptors (LXRs) act in concert to regulate ApoE expression and lipidation status. Increased ApoE expression results in enhanced Aß clearance and improved behavior in animal models of AD. PPARs and LXRs form obligate heterodimers with the retinoid X receptors (RXR) that comprise the active transcription factor. Thus, we reasoned that agonists of RXR might be more efficacious. Indeed, recent work has demonstrated that the RXR agonist bexarotene is remarkably effective in clearing amyloid from the brain and reversing a broad range of behavioral deficits in mouse models of AD.

Bexarotene as a potential therapeutic for Alzheimer’s disease and related disorders: We have focused our work on nuclear receptors owing to their ability to act broadly to regulate aspects of metabolism and immune function. First, we have recently recognized that in astrocytes the production of ApoE-based HDL particles is controlled through a linked metabolic pathway regulated by the nuclear receptors PPARγ:RXR and LXR:RXR. Thus, agonists of RXR might be expected to robustly stimulate ApoE expression, due to the activation of both receptor pairs by the RXR agonist. Indeed, bexarotene robustly stimulated ApoE/HDL levels in mice and this was associated with the rapid clearance of soluble forms of Aß. The reduced levels of Aß was correlated with improved memory and cognition, as demonstrated in three different animal models of AD using 5 different tasks. The nuclear receptors have a different effect on microglia, the brain’s tissue macrophage. In these cells, the nuclear receptors act to change their phenotype, promoting their polarization into an ‘alternatively’ activated state that represents induction of anti-inflammatory cytokines and genes associated with tissue repair. Importantly, the nuclear receptors promote phagocytosis, and in the AD brain this is associated with the phagocytic clearance of deposited forms of amyloid. Thus, stimulation of RXRs results stimulation of two distinct processes, both of which are disease modifying.

What next? We are currently investigating how best to deliver bexarotene. Our preliminary work demonstrates that the drug will be optimally efficacious at levels lower than the FDA-approved dosage. Moreover, we do not know how frequently to administer the drug to mice. This work is essential before advancing to Phase II clinical trials and will take some time to complete. We are also investigating new drug candidates.

Biology of the ERK MAP kinases
The laboratory has a long-standing interest in the roles of the ERK MAP kinases in the nervous system. We have developed murine lines in which ERK1 and ERK2 have been knocked out. Analysis of these mice has revealed unexpected roles for these enzymes in neural crest development, patterning of the developing brain and corticogenesis. The ERK knockouts phenocopy neuro-cardiofacial cutaneous, DiGeorge and related syndromes, and a subset of autism spectrum disorders, these syndromes arise from genetic perturbations of the ERKs or their upstream regulators. We are attempting to understand the mechanistic basis of these human disorders.

Gary and Julie