Newly discovered compounds also could provide more cancer treatment options

One of the key symptoms of many kinds of late-stage Alzheimer's disease is the creation of so called amyloid-beta (Aβ) plaques -- insoluble clumps of protein that deposit in the brain.  The culprit appears to be overactive epidermal growth factor receptor (EGFR), which tells nearby cells to constantly produce the plaque, preventing the body's natural healing mechanisms from carrying it away.

I. Cancer Drugs "Cure" Alzheimer's Symptoms in Flies and Rats

Cerrtain kinds of cancers also express EGRF, which contributes to their growth.  Two kinds of drugs -- erlotinib (Tarceva) and gefitinib (Iressa) -- have been found to suppress EGRF production, halting tumor growth and allowing the body's immune system to clear out the cancer.  Both drugs have a higher success rate that traditional chemotherapy, though some cancers mutate to achieve resistance to the EGRF inhibition. A third EGRF inhibitor drug -- AP26113 -- is showing great promise in clinical trials, even against the resistant mutation.

Putting two and two together, Professor Yi Zhong, Ph.D of Cold Spring Harbor Laboratory (CSHL) -- "a private, not-for-profit research and education institution at the forefront of molecular biology and genetics" -- used the two approved drugs (Tarceva and Iressa) in a clinical trial on fruit flies (Drosophila) and rats with Alzheimer's disease.

For the fruit fly trial, a human gene encoding Aβ-42 peptide -- a specific 42-amino acid kind of the plaque protein -- was inserted into the fly's genome to induce Alzheimer's.  While far "simpler" than the human brain, the fly's simple brain reacts similarly to the human brain when exposed to the plaque.  The genetically modified flies exhibited aberrant behavior associated with memory loss.  The flies were also genetically modified to increase EGRF production, which -- as in humans -- accelerated the plaque protein's production.

Fruit fly
When genetically modified with human EGRF promoting and plaque genes, fruit flies exhibit Alzheimer's symptoms just like humans. [Image Source: The Kitchn]

Dosing the flies with the EGRF blocking drugs the researchers saw the memory loss reversed, and the flies returned to their normal, healthy behavior.

II. New Compounds Work Even Better

Meanwhile, over in China Professor Yi's collaborators dosed memory-loss fruit flies with 2,000 synthetic candidate compounds, to try to find other EGRF blockers.  After two months of trials 45 promising compounds were identified.

Remarkably three of those not only were shown to reduce base EGRF production and memory loss in flies, they also prevented the plaque from promoting EGRF production in a positive feedback loop, a secondary form of inhibition.

Comments Professor Yi, "We were amazed to find that three of these compounds -- designated JKF-006, JKF-011 and JKF-027 -- not only showed effective results in rescuing memory loss in the mice, but also, in test-tube-based experiments prevented Aβ-42 from activating human EGFR."

Alzheimer's plaque
An amyloid plaque -- a key culprit in Alzheimer's disease [Image Source: CHSL]

The exact mechanism of the EGRF-induced brain damage is unknown, but Professor Yi suspects that it is pathological and not part of the standard cell death/aging process.  He states, "[The memory loss] may reflect the acute toxic effects of Aβ, which might be independent of synaptic and neuronal degeneration."

On a second set of trials on rodents he reports, "Eighteen days -- the shortest dosing period we tested -- was sufficient to reverse loss in these mice, although we should note that these animals had few morphological changes in the brain despite their severe memory loss when treatment began."

The results are thrilling in that they open the door to possibly turning off Alzheimer's disease and restoring the memory of many elderly patients to working order, using already available drugs.

Better still, the newly discovered compounds could offer more, better treatment options for both Alzheimer's and cancer patients, given their improved EGRF suppression.

The work was reported in the highly prestigious peer-review journal Proceedings of the National Academy of Sciences.

Source: CSHL

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