World Alzheimer’s Day: After 25 Years of Amyloid Hypothesis Research, Where Are We Now?

World Alzheimer’s Day: After 25 Years of Amyloid Hypothesis Research, Where Are We Now?
Twenty-five years have passed since researchers launched the idea that Alzheimer’s is a direct result of clumps of amyloid-beta littering the brain. The amyloid hypothesis of Alzheimer’s disease, as it is called, quickly raised hopes among researchers and patients alike that the dreaded disease would soon be under our control. But a cure seems as distant today as it did then. So what have researchers concluded over the last 25 years, and why is the progress here so slow when other research fields are advancing by leaps and bounds?

The complex reality of simplicity

The amyloid hypothesis of Alzheimer’s disease was simple. An imbalance in the production or removal of amyloid-beta was said to cause an accumulation and clumping of the peptide in the brain, which was toxic in itself and, in turn, set off a cascade of events leading to neurodegeneration and loss of brain tissue. So if patients dying of Alzheimer’s disease have brains full of a protein that kills their nerve cells, the problem should be easily solved by removing the protein, researchers believed. The idea born in the early 1990s was that if researchers learned the molecular secrets of the protein — asking questions like ‘what makes it aggregate,’ or ‘in what way does it kill neurons’ — it would just be a matter of time before a treatment, or even cure, could be developed. Unfortunately, the simple idea turned out to be a lot more complex than scientists imagined. Studies of protein aggregation are arduous and slow tasks. The problem with protein aggregation is that, in contrast to studies of other cellular processes or structures, evolution has wor
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  1. Alzheimer's researcher says:

    It has actually been 32 years since George Glenner first proposed the amyloid hypothesis of Alzheimer’s disease. It was reiterated in light of the gene mutations later on (25 years ago).

  2. Lane Simonian says:

    This is one of the best articles that I have read on amyloid and Alzheimer’s disease in several years. In my twelve years of studying Alzheimer’s disease as a non-scientist (although with some background in biology), I have come to the conclusion that oxidative stress is the true cause of Alzheimer’s disease. The following chart and quote help lay out the case.

    “Malinow’s team found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then, when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words, amyloid beta doesn’t inhibit brain function unless PKC alpha is active.”

    I am a visual person, so it might help for some readers to print out the chart to follow the rest.

    Protein kinase C leads to the secretion of the amyloid precursor proteins, caspase 3 leads to the first cut in the amyloid precursor protein (the beta secretase cut), intracellular calcium release leads to the second cut in amyloid (the gamma secretase cut which leads to amyloid oligomers) and to hyperphosphorylated tau, and peroxynitrite mediated nitration of amyloid oligomers leads to amyloid plaques and to nitrated tau proteins. The amyloid precursor protein and amyloid oligomers further activate protein kinase C via increasing g protein signalling. However, many other factors increase this signalling including the ApoE4 gene, psychological stress, various environmental toxins (such as various pesticides, air pollutants, and industrial solvents), and moderate to heavy smoking. Mice don’t replicate the degree of oxidative damage found in humans with Alzheimer’s disease, they simply replicate the oxidative damage produced by the amyloid precursor protein and amyloid oligomers (and perhaps by stress).

    The key pathway in Alzheimer’s disease is protein kinase C activation, NMDA receptor activation, and peroxynitrite and caspase 3 formation. Nitro-oxidative stress produced by peroxynitrite inhibits the synthesis and release of neurotransmitters involved in short-term memory, sleep, mood, social recognition, and alertness, inhibits neurotransmissions, limits the flow of blood and inhibits the transport of glucose in the brain which can lead to delusions, at high levels (due to psychological stress) peroxynitrite contributes to agitation, aggression, and hallucinations, prevents the regeneration of neurons in the hippocampus, and in conjunction with caspase 3 causes the death of neurons.

    Peroxynitrite exhausts the brain own master antioxidant–glutathione. To treat the disease, external antioxidants must be used. The most effective of these are eugenol found in various essential oils via aromatherapy (Jimbo, et al. 2009) and syringic acid and ferulic acid in panax ginseng (Heo, et al. 2011 and 2012).

    Removing amyloid oligomers does very little to treat Alzheimer’s disease because it removes only one source of oxidative stress (and removing amyloid plaques probably does even less). To treat the disease, one needs to scavenge peroxynitrite and reverse part of the nitro-oxidative damage that it has done to the brain.

  3. Dante Marciani says:

    Excellent analysis of the amyloid-beta hypothesis status. In fact, plaque seems to a protective mechanism, while there is increasing evidence that the smaller soluble amyloid oligomers are highly neurotoxic. Yet, with the exception of aducanumab, none of the drugs tested target those oligomeric forms, which may explain the consistent clinical failures. An interesting observation is that amyloid may not be the single causal agent, indeed, new findings indicate that amyloid may the triggering agent, but that it has many partners in crime, like tau, neuroinflammation and others; hence, a multi-prong approach may be therapeutically much more effective. As the article concludes, considering the complexities of this disease, keeping an open mind is the best approach to study and solve the problem.

    • Tim Bossie says:

      Thank you for the very thought out and detailed response to this post. We are glad that you liked it and are appreciative of your insight. Thanks!

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