Karl Herrup got it right with his novel hypothesis on Alzheimer’s disease (AD). The two main brain pathological lesions associated with AD—the many forms of oligomeric Aβ and tau aggregates—most likely are not the cause, but the response to an injury. According to Herrup, the initiating injury is “some event—a physical trauma, a major illness or infection, a vascular event (possibly so small as to be clinically detectable), metabolic stress [...], or even the stress associated with a major life event such as a death in the family,” Under normal conditions, i.e., at a young age and in the absence of susceptibility factors, including genetic ones, not much happens: The brain injury caused by these events is silently corrected by the normal response that nature has evolved for that purpose. What old age brings is an increased frequency of such injuries, and—with that—a prolonged response to correct these injuries. It is the persistent response, not the injury, that now leads to plaques, tangles, attempts to re-enter the cell cycle, synaptic dysfunction, and, finally, neuronal death.
At two recent meetings (Society for Neuroscience and the American Society for Cell Biology), we presented a similar view on AD, describing one way by which normal aging could lead to a persistent endoplasmic reticulum (ER) stress response, which is normally aimed at correcting a slightly slowed-down axonal transport. According to our hypothesis, this response leads to the generation of Aβ in the ER, as a protective mechanism, and is not intended to last long. It is the prolonged activation of this stress response, caused by a chronically slowed-down axonal transport at old age, which results in accumulation and oligomerization of Aβ within the neuron.
This novel view of AD also brings us back to the philosophical question of to what extent AD can be regarded as a normal process of aging. Oxidative stress, the accumulation of material that is normally cleared from the brain, and slower axonal transport are all part of the process of normal aging. Many of the initiating injuries—as Karl Herrup defines them—are part of normal life. The response to injury is also normal. And yet, all these “normal” things lead to disease.
It may be that a cure for AD is still far away. However, what this new view of AD now offers are multiple ways to prevent the disease. How? 1) By slowing down the aging process; 2) by minimizing the probability for initiating injuries; and 3) by preventing the normal response to the injury from happening. Maybe the organism will better tolerate a slightly slowed-down axonal transport than the damage wreaked by a persistently activated mechanism to correct that transport. There is certainly a lot of work to do to examine the multiple forms of injury, the responses they elicit, and the specific therapeutic and prevention approaches. The show goes on (pending funding)!
References: Muresan, V., and Muresan, Z. Alzheimer’s Amyloid-beta Precursor Protein (APP) Is a Sensor that Detects Variations in Kinesin-1 Levels, and Signals to the Nucleus Abnormalities in Axonal Transport. Annual Meeting of the Society for Neuroscience, San Diego, November 13-17, 2010.
Muresan, V., and Muresan, Z. Alzheimer’s Amyloid-beta Precursor Protein (APP) Triggers an Endoplasmic Reticulum (ER) Stress Response to Impeded Axonal Transport, by Sensing Variations in Somatic Levels of Kinesin-1. 50th Annual Meeting of the American Association for Cell Biology, Philadelphia, December 11-15, 2010.
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Rutgers - New Jersey Medical School
Karl Herrup got it right with his novel hypothesis on Alzheimer’s disease (AD). The two main brain pathological lesions associated with AD—the many forms of oligomeric Aβ and tau aggregates—most likely are not the cause, but the response to an injury. According to Herrup, the initiating injury is “some event—a physical trauma, a major illness or infection, a vascular event (possibly so small as to be clinically detectable), metabolic stress [...], or even the stress associated with a major life event such as a death in the family,” Under normal conditions, i.e., at a young age and in the absence of susceptibility factors, including genetic ones, not much happens: The brain injury caused by these events is silently corrected by the normal response that nature has evolved for that purpose. What old age brings is an increased frequency of such injuries, and—with that—a prolonged response to correct these injuries. It is the persistent response, not the injury, that now leads to plaques, tangles, attempts to re-enter the cell cycle, synaptic dysfunction, and, finally, neuronal death.
At two recent meetings (Society for Neuroscience and the American Society for Cell Biology), we presented a similar view on AD, describing one way by which normal aging could lead to a persistent endoplasmic reticulum (ER) stress response, which is normally aimed at correcting a slightly slowed-down axonal transport. According to our hypothesis, this response leads to the generation of Aβ in the ER, as a protective mechanism, and is not intended to last long. It is the prolonged activation of this stress response, caused by a chronically slowed-down axonal transport at old age, which results in accumulation and oligomerization of Aβ within the neuron.
This novel view of AD also brings us back to the philosophical question of to what extent AD can be regarded as a normal process of aging. Oxidative stress, the accumulation of material that is normally cleared from the brain, and slower axonal transport are all part of the process of normal aging. Many of the initiating injuries—as Karl Herrup defines them—are part of normal life. The response to injury is also normal. And yet, all these “normal” things lead to disease.
It may be that a cure for AD is still far away. However, what this new view of AD now offers are multiple ways to prevent the disease. How? 1) By slowing down the aging process; 2) by minimizing the probability for initiating injuries; and 3) by preventing the normal response to the injury from happening. Maybe the organism will better tolerate a slightly slowed-down axonal transport than the damage wreaked by a persistently activated mechanism to correct that transport. There is certainly a lot of work to do to examine the multiple forms of injury, the responses they elicit, and the specific therapeutic and prevention approaches. The show goes on (pending funding)!
References:
Muresan, V., and Muresan, Z. Alzheimer’s Amyloid-beta Precursor Protein (APP) Is a Sensor that Detects Variations in Kinesin-1 Levels, and Signals to the Nucleus Abnormalities in Axonal Transport. Annual Meeting of the Society for Neuroscience, San Diego, November 13-17, 2010.
Muresan, V., and Muresan, Z. Alzheimer’s Amyloid-beta Precursor Protein (APP) Triggers an Endoplasmic Reticulum (ER) Stress Response to Impeded Axonal Transport, by Sensing Variations in Somatic Levels of Kinesin-1. 50th Annual Meeting of the American Association for Cell Biology, Philadelphia, December 11-15, 2010.
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