Alzheimer's Disease

The primary emphasis of preclinical research is to understand how the disease operates — from the mechanism of damage to repair. These research projects include the study of:

• Regenerative medicine
• Angiotensin-converting enzyme
• Age-related immune cells
• Insulin resistance

We are studying abnormalities in the function of monocytes and macrophages — two types of immune system cells capable of removing amyloid beta (Aβ). Our researchers hypothesize that these cells do not function efficiently in Alzheimer's patients, allowing amyloid accumulation, eventual nerve cell loss and cognitive deterioration. We generate a supply of monocytes and macrophages from patients to study their cells' ability to clear toxic forms of Aβ and resist its detrimental effects.

• Principal Investigator: Helen Goodridge, PhD

Researchers investigate how targeting over-expression of angiotensin-coverting enzyme (ACE) by macrophages can change the course of Alzheimer's progression. In experimental models, ACE has been shown to be critical in destroying soluble levels of pathogenic Aβ1-42, altering inflammatory responses and preventing cognitive decline.

The research team seeks to determine if ACE can help immune cells eradicate and resist damaging forms of Aβ.

• Principal Investigators: Kenneth Bernstein, MD, and Maya Koronyo-Hamaoui, PhD

Using a recreation of homeostatically expanded CD8 T cells, researchers are investigating causes of sporadic Alzheimer's and also new treatments for the disease. In experiments, these cells assume characteristics of aberrant T cells that accumulate with aging in some individuals. Aberrant T cells are unique because of their functional abilities and conditions favoring their formation with age and traumatic brain injury.

Recipients of these aberrant T cells show signs of pathological hallmarks of Alzheimer's, including Aβ plaques, neurofibrillary tangles, neuronal and synaptic loss, progressive brain atrophy, and profound cognitive impairment. In an effort to determine the functional properties of aberrant T cells promoting this neuropathology, we also recreate homeostatic expansion using T cells deficient in their two major effector functions: target cell lysis (perforin deficiency) and pro-inflammatory cytokine production (IFN-gamma deficiency). These T cells expand normally, but they either fail to persist in the brain, causing neuropathology (deficient T cells), or they enter the brain but promote only limited neuropathology without clinical symptoms.

Our findings suggest that aberrant T cells linked to at least two major risk factors induce the major hallmarks of sporadic Alzheimer's. These T cells may therefore be linked to development of Alzheimer's in patients, a possibility we are seeking to validate. Our research also provides a unique model to further examine sporadic pathoetiology of Alzheimer's, neurodegeneration and therapy, as well as the general contribution of immune aging to diseases.

• Principal Investigator: Christopher Wheeler, PhD

To reduce and reverse the brain pathology and cognitive deficits characteristic of Alzheimer's, our researchers experiment with FDA-approved antidiabetic drugs known as incretin agonists — exenatide (Byetta) and liraglutide (Victoza). Utilizing results of early clinical trials and other experimental methods, we seek to identify:

• Molecular mechanisms by which brain insulin resistance develops in mild cognitive impairment, Alzheimer's disease dementia and Parkinson's disease
• Molecular mechanisms by which such resistance impairs neuronal function, especially synaptic activities critical to learning and memory
• The relationship of brain insulin resistance to insulin resistance outside the brain in obesity and type 2 diabetes
• Mechanisms by which incretin agonists improve neuronal insulin responsiveness
• The most potent, yet safe incretin agonist treatments for brain insulin resistance in Alzheimer's disease

The hope is these already FDA-approved drugs will be available as therapeutic agents for Alzheimer's within five years.

Our clinical trials focus on early diagnosis and immune-based therapies. Currently there are two trials to examine:

• Immune-modulation Alzheimer's
• Utilizing a retinal imaging device for early diagnosis

Researchers are refining a noninvasive, in vivo optical imaging test to monitor discrete plaque dynamic appearance and clearance in human retinas. The test has proven successful in detecting early signs of Alzheimer's in preclinical experiments. The ability to identify Alzheimer's in human retinas has the potential to revolutionize how we detect early signs of the disease. Our studies also suggest using retinal imaging alongside immune-based therapies to determine which interventions increase the likelihood of significantly retarding and treating Alzheimer's.

• Principal Investigators: Keith L. Black, MD, Maya Koronyo-Hamaoui, PhD, and Yosef Koronyo, MSc, LLB

On retina research, our researchers collaborate with:

• Department of Pathology and Laboratory Medicine
• Department of Neurology
• Keck School of Medicine of USC

On immune based-based treatments (Copaxone), we collaborate with:

• Department of Neurobiology at the Weizmann Institute of Science in Rehovot, Israel

We also collaborate with UCLA's Department of Neurology, Molecular Biology Institute and Brain Research Institute, Biopolymer Laboratory and Mary S. Easton Center for Alzheimer's Disease Research.

• Bernstein Laboratory
• Goodridge Laboratory
• Koronyo-Hamaoui Laboratory