Protein Aggregates of Alzheimer's Disease Observed in Aged Dolphins

What can we learn from the observation that very few other mammalian species exhibit the protein aggregates associated with Alzheimer's disease, the characteristic amyloid-β plaques and tau neurofibrillary tangles? There is debated evidence of amyloid in some primate species other than our own, and a study published earlier this year was the first to claim both amyloid and tau in old chimpanzee brains. Primates do not seem to suffer the widespread death of brain cells that occurs in humans, however, amyloid or no amyloid. In short-lived mammals such as rodents there is little sign of this sort of protein aggregation at all. When researchers are said to study Alzheimer's disease in mice, they are in fact studying one of a number of very artificial biochemistries, genetically engineering lineages given conditions that resemble Alzheimer's in some ways - but these conditions are not actually Alzheimer's. Alongside the enormous complexity of the biochemistry involved, with mapping of the brain and the cell taking place alongside investigation into its failure with age, this artificiality of the mouse models, the fact they are so very different from human Alzheimer's, is one of the reasons why there is a high rate of failure in moving from animal research to human medicine in neurodegenerative research.

In the research noted here, the authors show evidence for dolphins to exhibit both amyloid and tau, making them only the second mammalian species for which this the case. The publicity materials claim it to be the only species, but this is fair enough given that it is only a couple of months since the chimpanzee research was published - that sort of outdated claim is fairly commonplace given that papers can take a year to get through peer review, and months in the final passage to publication. Why humans, dolphins, and chimpanzees, however? Why not mice and horses? This probably ties back in to the question of why longer-lived mammals are longer-lived - what exactly are the biochemical switches and dials involved in this difference? It is of particular interest for our understanding of human evolution because our longevity is comparatively recent, a point of branching from our near primate cousins that may be connected with selection pressures associated with our greater intelligence. Intelligence allows for culture, collaboration, and the Grandmother effect, in which older individuals can help to ensure that their descendants prosper, and thus a longer life is selected for. Should we expect this in dolphins? Data supports the presence of the Grandmother effect in killer whale communities, so it doesn't seem far-fetched.

In the research materials here, it is speculated that some large fraction of the metabolic reactions to calorie restriction, that extend life by up to 40% in mice, have evolved to be switched on all the time in humans and other longer-lived mammals. If the case, this would explain why calorie restriction has only a modest effect on life span in humans - some currently unknown size of benefit that cannot be much larger than a few years, or it would have been noted, measured, and recorded long ago. One counter-argument is that the short term response to calorie restriction in humans is beneficial and looks very similar to that of mice - humans clearly can obtain health benefits through the practice of calorie restriction, and thus perhaps we need to look elsewhere in our biochemistry for an explanation of the sizable difference in outcomes for longevity.

Dolphin brains show signs of Alzheimer's Disease

"It is very rare to find signs of full-blown Alzheimer's Disease in non-human brains. This is the first time anyone has found such clear evidence of the protein plaques and tangles associated with Alzheimer's Disease in the brain of a wild animal." Humans are also almost unique in living long after they are capable of having children; fertility in both men and women declines sharply around the age of 40, but people can go on to live as long as 110 years. Other animals tend to die shortly after the end of their fertile years. Researchers tested the idea that living long after the end of fertility might be linked to Alzheimer's Disease, by studying the brains of another species which can live long after having offspring: dolphins. They found signs of Alzheimer's Disease in the brains of dolphins which had died after washing up ashore on the Spanish coast.

The team analysed 'plaques' of a protein called beta amyloid in the brains of dolphins, as well as tangles of another protein called tau: these plaques and tangles are signatures of Alzheimer's Disease. The team think that humans and dolphins are near-uniquely susceptible to Alzheimer's Disease because of alterations in how the hormone insulin works in these species. Insulin regulates the levels of sugar in the blood, and sets off a complex chemical cascade known as insulin signalling. While alterations in insulin signalling can cause diabetes in people and other mammals, previous scientific work also found that extreme calorie restriction in some animals (e.g. mice and fruit flies) altered insulin signalling - and extended the animals' lifespan by up to three times.

"We think that in humans, the insulin signalling has evolved to work in a way similar to that artificially produced by giving a mouse very few calories. That has the effect of prolonging lifespan beyond the fertile years, but it also leaves us open to diabetes and Alzheimer's Disease. Previous work shows that insulin resistance predicts the development of Alzheimer's Disease in people, and people with diabetes are more likely to develop Alzheimer's. But our study suggests that dolphins and orcas (who also have a long post fertility life span) are similar to humans in many ways; they have an insulin signalling system that makes them an interesting model of diabetes, and now we have shown that dolphin brains show signs of Alzheimer's identical to those seen in people."

Alzheimer's disease in humans and other animals: A consequence of postreproductive life span and longevity rather than aging

Alzheimer's disease and diabetes mellitus are linked by epidemiology, genetics, and molecular pathogenesis. They may also be linked by the remarkable observation that insulin signaling sets the limits on longevity. In worms, flies, and mice, disrupting insulin signaling increases life span leading to speculation that caloric restriction might extend life span in man. It is our contention that man is already a long-lived organism, specifically with a remarkably high postfertility life span, and that it is this that results in the prevalence of Alzheimer's disease and diabetes. We present novel evidence that Dolphin, like man, an animal with exceptional longevity, might be one of the very few natural models of Alzheimer's disease.

Comments

A good case for pleiotropic antagonism if it is true.
Hopefully the observations can be confirmed in the near future so the field can move past insulin signaling pathways ... not that they have a shortage of completely useless pathways from short lived animals to test at this point.

"it's not a disease of aging it's a disease of long life" - that's a good way to say nothing.

Posted by: Anonymoose at October 24th, 2017 8:08 PM

Did the dolphins beach themselves because they had Alzheimer's?

Posted by: gwood at October 24th, 2017 9:50 PM

Is there any AD research that uses organoids?

Posted by: Antonio at October 25th, 2017 2:00 AM

It is more likely that shorter lived species just don't have time to build up insulin resistance or protein aggregates, despite a faster metabolic rate and higher ROS generation, etc.

'Other animals tend to die shortly after the end of their fertile years' - yes, but this is due to the harsh realities of life in the wild. Many animals can live twice as long in a zoo. Before the advent of civilization, agriculture, etc., most humans wouldn't have lived much past their twenties either.

Posted by: Mark at October 25th, 2017 3:16 AM

the paper's results were based on pathology on 8 dolphins. I'm glad they published this, but I find it fact free (no criticism intended) on informing existence of an actual disease state - much less disease states analogous to humans. 8 specimens is too few. No knowledge of the autopsied organism's ages as far as I could see from the paper. No mention of other beached dolphins found at the same times/places against which the reported dolphins could be compared.

The authors then proceed to recommend against pursuing their line of research in captive animals. I agree that it is good to avoid invasive physical experimentation on these animals. But it seems quite short sighted to me in post-mortem since it is only in captive animals that we'd have a prayer of being able to systematically observe behavioral changes over time which could then be correlated to disease states post-mortem.

Posted by: David Gobel at October 26th, 2017 1:51 PM

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