Radicals and Aging: More Complicated Than We Thought
A study published in 2006 by Quebec researcher Serge Rivest and his team marked a significant breakthrough, contradicting some generally accepted ideas while still remaining within the framework of the amyloid hypothesis.
This study was based on the observation that the brain’s defence cells, the microglia,
accumulate around amyloid plaques but seem unable to eliminate them. This observation gave rise to the the generally accepted idea of a subsequent inflammation that ends up killing the neurons.
The prescription of anti-inflammatory drugs to people with Alzheimer’s is attributable to this interpretation of the phenomenon.
But for Rivest and his team, the microglia are not part of the problem, but rather part of the solution. Because while the microglia in the brain struggle to contain the amyloid plaques, the microglia that come from the stem cells in the bone marrow manage to destroy these plaques far more effectively. The reason that Alzheimer’s
develops anyway is not clear. Part of the explanation seems to be that when the plaques first start forming, the process by which the stem cells migrate through the bloodstream to the brain and there turn into microglia is not yet activated.
And later. when the plaques have become numerous, the process is active but no longer sufficient to contain them.
The new treatment approach therefore is to stop administering anti-inflammatories, which can only interfere with this natural means of defence, and instead develop ways of making the microglia from the bone marrow work harder. One approach now being tested with mice that may one day be used in humans is to remove stem cells from the patient, enhance them through genetic manipulation, and then reinject them into the same patient, with no risk of rejection as foreign bodies. Researchers are testing various methods of making these microglia more effective—for example, by increasing their affinity for the plaques or by making the plaques more readily assimilable by digestive enzymes.
|AMYLOID PLAQUES AND NEUROFIBRILLARY TANGLES
Research on Alzheimer’s has been largely dominated by what was initially known simply as the amyloid hypothesis and is now more specifically described as the beta-amyloid synaptic hypothesis. According to this hypothesis, the abnormal accumulation of beta-amyloid protein, in the form of amyloid plaques or oligomers,
in the brain, is the primary mechanism that causes Alzheimer’s. The majority of experimental vaccines and medications therefore target these amyloid plaques.
Within the Alzheimer’s research community, scientists whose research is based on this hypothesis are known as “BAPtists” (where BAP stands for beta-amyloid
peptide). The primary opposing camp are the TAUists, who instead believe that Alzheimer’s disease develops as the result of the appearance of neurofibrillary tangles.
Left: amyloid filaments
helical filaments (PHFs) and their components,
But the TAUists are not the only scientists who question the amyloid hypothesis. More and more researchers are beginning to voice alternative explanations. To justify their explorations off the beaten path, these scientists point out that the quarter-century history of research based on the amyloid hypothesis is littered with failures, with little tangible progress to show for it. Here is a brief summary of the flaws that these researchers see in this hypothesis.
First, very little correlation has
been observed between the extent of cognitive deficits in Alzheimer’s patients and the quantity of amyloid plaques in their brains.
This represents a major anomaly in this paradigm that has dominated Alzheimer’s research since the start of the 1990s, if not longer.
The second perceived flaw is that amyloid plaques are also found in the brains of normal individuals, something that the defenders of the amyloid hypothesis are hard-pressed to explain. In fact, “normal” brains can sometimes contain more amyloid plaques
than the brains of patients with severe cases of Alzheimer’s. Hence Whitehouse and other authors have argued that the criteria for diagnosing “Alzheimer’s disease” are too vague and that Alzheimer’s cases may be nothing more than special cases of normal aging.
Third, the relations between beta-amyloid protein and tau protein are complex, to say the least. Some authors say that people with Alzheimer’s-type dementia actually have two kinds of cortical pathologies—beta-amyloid and tau—simultaneously, that there is a synergy between the two, and that there is therefore no need to choose between the BAPtist and the TAUist camps. And there are in fact some data to support this view. For example, a transgenic mouse that overexpresses both beta-amyloid
protein and tau protein will produce more neurofibrillary tangles than a transgenic mouse that has only the tau-protein mutation.
But the overall picture remains unclear. For example, normal people can have only moderate levels of beta-amyloid
deposits but at the same time have fairly extensive neurofibrillary tangles, advancing all the way into the temporal cortex in stage
6 or 7 tau pathology. And here again, cases have been reported of patients who had up to stage 6 tau pathology but no beta-amyloid deposits.
Moreover, individuals age 75 and over always have some tau pathology in their transentorhinal and entorhinal cortex. But this pathology is often quite limited, and there are even people in their 90s who display very little tau pathology. This shows once again that the development of this pathology is not correlated with age in any linear, systematic way, although age is a major risk factor for tau pathology.
Many researchers in fact believe that accumulations of proteins are generally only the final manifestations of diseases with earlier causes, and that amyloid plaques and neurofibrillary tangles are no exception to this rule. Some researchers even directly question the harmfulness of amyloid plaques and neurofibrillary tangles, arguing that they may in fact represent a defensive response by the brain to harmful processes that precede them, such as oxidative stress,
inflammation, and dysfunctions in the cellular cycle.
Thus, in contrast to the assumption, under the amyloid hypothesis, that beta-amyloid protein has no particular physiological function, many studies now report that beta-amyloid
binds to specific receptors or can induce inflammatory reactions. For example, in vivo studies have shown that this protein plays a protective role against microbes.
But even though beta-amyloid may contribute to a normal, helpful immune response in the short term, its prolonged activity might still have pathological consequences.
Credit: Delphine Bailly, NEUR-ONES
|If that is so, then we are back to the assumption of beta-amyloid toxicity that is implicit in the beta-amyloid hypothesis, and hence back to the idea that we should develop strategies to eliminate beta-amyloids in the brain. In other words, we come to the opposite conclusion from those who believe that the inflammatory response is beneficial and that instead of trying to reduce it with medications, we should instead be trying to potentiate the work of the microglial cells (see sidebar).
And what about the protective antioxidant properties that 40-amino-acid beta-amyloid has been shown to have? This finding, like many others, argues against the oxidative damage of Alzheimer’s that is attributed to beta-amyloid in the amyloid hypothesis (see box below).
In any case, all of these “abnormal” data (in the Kuhnian sense) tend to weaken the amyloid hypothesis, which some authors say had begun to take on the trappings of dogma. Because dogmatism is a bad idea in general, and a bad idea in science in particular, many researchers are rather pleased to see the growing number of alternative hypotheses to help us better understand and treat the condition known as Alzheimer’s.
These researchers also hope that research-funding agencies and scientific journals will do more to encourage the emergence of such hypotheses—something that they have not always done in the past.
Beyond its academic sociological interest, this is a major societal issue, considering the resources invested in developing treatments based on the amyloid hypothesis and the hopes that such treatments arouse in people with Alzheimer’s and their families.
Oxidative stress is one of the harmful mechanisms attributed to amyloid plaques under the amyloid hypothesis, although contradictory results have been reported. The plaques apparently release molecules of hydrogen peroxide (H2O2) that quickly break down into two hydroxide (OH) ions.
These ions are described as free radicals, because they try to bind their free electron by extracting a hydrogen atom from the neuron’s cell membrane. (This membrane is composed of carbon-based molecules containing numerous hydrogen atoms.) The “hole” thus created in the membrane then lets other free radicals penetrate inside the neuron, where they attack its DNA, disrupting the cell functions associated with this genetic information.