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case western reserve university

THE LANDRETH LAB

 

Students

Brad Casali:

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by memory loss and cognitive decline. One pathological hallmark of AD includes extracellular aggregation of amyloid beta (Aß) plaques. Elevated Ab levels result from age related impaired clearance and are responsible for cognitive impairment and memory loss, ultimately resulting in neuronal death. We have shown that bexarotene, a selective selective retinoid-X-receptor (RXR) agonist, increases expression of highly lipidated ApoE-containing high density lipoprotein (HDL) particles, resulting in reduced Aß levels and enhanced cognitive function in mouse models of AD. Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid in the brain, and low levels of brain DHA have been correlated with a variety of neurological symptoms including cognitive impairment. Indeed, AD brains show lower DHA levels than aged-matched controls. Since DHA is also a known RXR ligand, we hypothesized that dual combination of bexarotene and DHA could synergize to promote increased clearance of Aß peptides and improved cognitive function in the 5XFAD mouse model of AD. We propose the synergistic mechanism is enhanced production of highly lipidated ApoE-containing HDL particles. We are also exploring whether insoluble, plaque-associated Aß species or the soluble Aß species are ultimately responsible for improved cognitive function despite bexarotene discontinuation in a mouse model of AD. Both of these projects will help us to understand not only the broader influence of Aß species in the brain on cognitive function, but also the potential combinatorial effects of drug treatments of the amelioration of AD.

Taylor Jay:

Just as I was joining the lab, new genetic variants of the triggering receptor expressed in myeloid cells 2 (Trem2) gene were shown to confer high risk for developing Alzheimer’s disease (AD). As its name suggests, Trem2 encodes a receptor that’s exclusively expressed on immune cells. For labs like ours that are interested in how immune cells contribute to AD pathogenesis, this discovery was very exciting. It meant that by understanding more about Trem2 expression and function, we would be able to understand which immune cell subsets and which aspects of their function are important in actively modulating AD pathology. In our AD mouse models, we found that Trem2 was exclusively expressed by myeloid cells associated with amyloid plaques. Surprisingly, based on marker expression, these cells appeared to be derived from peripheral monocytes rather than the brain resident immune cell population, microglia. We found that in AD mice lacking Trem2 expression, these plaque-associated, potentially peripherally-derived cells, were absent from the brain. Loss of these cells was also associated with reduced inflammation in the brains of AD mice. Our recent work demonstrates that Trem2-deficient AD mice also have time-dependent alterations in amyloid pathology, suggesting that these cells play an active role in the modifying the deposition and clearance of amyloid plaques. Moving forward, we’ll be looking at the mechanisms by which Trem2 deficiency results in a loss of plaque-associated myeloid cells and alters pathology.

Becki Courtney:

One of the characteristics of the Alzheimer’s disease (AD) brain is the accumulation of amyloid ß (Aß) in the brain. Our lab has recently found that treatment of mouse models of AD with agonists of Liver X Receptors (LXRs), results in the proteolytic degradation and clearance of Aß from the brain. LXRs form obligate heterodimers with other nuclear receptors to form transcriptionally active complexes which drive the expression of genes, such as ApoE and the lipid transporter ABCA1, that function in Aß clearance. The capacity of ApoE to facilitate Aß degradation is dependent not only on ApoE isoform but also on its lipidation status, which is determined by ABCA1 activity. LXR agonists act to increase clearance of Aß by driving the expression of ABCA1 and ApoE. I am interested in the therapeutic potential of LXR agonists in AD mouse models, and how to administer these agonists to achieve the greatest benefit.

Caitlin Quigley

Paul Chen