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I have known Eliezer for many years. The BSF grant finally gave us the opportunity to collaborate and translate into reality many ideas we had been discussing."
Prof. Eliezer Masliah: Department of Neurosciences, University of California at San Diego
"This collaborative BSF grant between Tel Aviv University and UCSD allowed me to greatly advance our research in the area of synaptic degeneration in AD through the new animal model developed by Dr. Michaelson. Above all, the BSF grant has strengthened the scientific ties between our laboratories. The friendship with Danny also led to other new relationships and collaborations with scientists in Israel. Since Prof. Michaelson serves on the Organizing Committee of the “International Conferences on Alzheimer's Disease and Related Disorders (ICAD), the BSF grant also gave me the opportunity of attending these Meetings. As a Jew in the Diaspora, visiting Israel is always a very significant experience -- meeting old and new friends and relatives, and seeing the amazing developments in the land of milk and honey."
The genetic forms of AD (Alzheimer’s Disease), which is the most common form of dementia among the aged population, are associated with mutations in the gene coding for apoE4 (apolipoprotein E). As in sporadic (non-genetic) AD, elevated brain β-A (β-amyloid) damages the synaptic connections between neurons. This suggests that cross-talk between apoE4 and β-A accentuates the pathological effects of AD. The enzyme neprilysin, which degrades β-A, also plays an important regulatory role. Profs. Masliah and Michaelson have developed the first in vivo animal model for studying these interactions in the early stages of AD. It is hoped that this might eventually generate new therapeutic leads for treating human AD.
Cooperation In their BSF-supported research, Profs. Michelson and Masliah sought to shed light on the relationship between β-A and apoE, two key players in AD pathogenesis. Together, they developed the first in vivo NDD model system in mice, which is uniquely suited for studying the interactions among these systems in the early stages of AD. Findings Prof. Michaelson’s group recently showed that inhibition of neprilysin specifically enhances β-A aggregation only in apoE4 (but not in normal apoE3) mice. In further experiments using these animal models, β-A accumulation was found to lead to cell death (apoptosis) in the hippocampus, which plays a crucial role in memory and spatial navigation and is among the first brain regions to suffer damage in AD. Moreover, these effects are associated with pronounced cognitive deficits, indicating hippocampal dysfunction (as measured by performance in the dry-maze behavioral test).
In brain sections sent to Prof. Masliah’s laboratory, state-of-the-art laser confocal and electron microscopic analysis was carried out. He found β-A deposits in the hippocampal CA1 neurons correlated with enhanced activation and leakage of lysosomes (organelles containing enzymes that break down cell parts and molecules). This is associated with cross-talk between the β-A and apoE pathways. Novel pharmacological strategies and agents, based on these findings, are now being developed in both laboratories.
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ANIMAL MODEL FOR MONITORING THE EARLY INTERACTIONS INVOLVED IN ALZHEIMER’S DISEASE (AD) |
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Prof. Daniel Michaelson: Department of Neurobiochemistry, Tel Aviv University
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Lysosomal Localization of β-A in Hippocampal CA1 Neurons of apoE3 and apoE4 Mice Following Inhibition of Neprilysin |
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Laser confocal images: the lysosomal marker cathepsin-D (red, left panels), β-A (mAb 4G8) (green, center panels), and merged images (right panels). |
