Castellani RJ, Lee HG, Zhu X, Nunomura A, Perry G, Smith MA.
Neuropathology of Alzheimer disease: pathognomonic but not pathogenic.
Acta Neuropathol. 2006 Jun;111(6):503-9.
PubMed.
I agree with the main thesis of this paper, that the lesions associated with dementia by Alois Alzheimer 100 years ago are latecomers in the pathophysiology of AD. It has become clear that manifestations of Aβ other than the plaque are major culprits and also that there are other molecules vitally involved in disease pathophysiology.
This paper is a solid confirmation of many previous human autopsy studies that showed there is little correlation between the visible AD lesions and rates of dementia. The feedback relationships among amyloid and NFT pathology and toxic metals in dementia should be included in future investigations. Van Rensburg et al. found that amyloid and aluminum bond to each other to quench each other's oxidative toxicity, which is not surprising, as APP is a copper shuttle. The plaques may be a protective sequestration mechanism for both.
References:
van Rensburg SJ, Daniels WM, Potocnik FC, van Zyl JM, Taljaard JJ, Emsley RA.
A new model for the pathophysiology of Alzheimer's disease. Aluminium toxicity is exacerbated by hydrogen peroxide and attenuated by an amyloid protein fragment and melatonin.
S Afr Med J. 1997 Sep;87(9):1111-5.
PubMed.
This is a critical review emphasizing the pivotal role of oxidative stress in the pathogenesis of AD, based on the frequently published notion of the authors that both Aβ deposition and tau pathology represent the sequelae and not the causes of oxidative stress and oxidative modification of cytoskeletal proteins, leading to tau phosphorylation. It also emphasizes that extensive Aβ deposits are signals not of neurotoxicity per se but of oxidative imbalance and are oxidative stress responses. However, this concept does not take into consideration the multiple other noxious factors known to be active in the complex pathogenic cascade of AD and other neurodegenerative disorders, for example, reduced cerebral energy and glucose metabolism related to disorders of insulin receptor transduction pathways; dysfunction of mitochondria leading to cellular bioenergy crisis; misfolding and accumulation of insoluble proteins—probably as a means to protect cells from toxic protein influences and to delay cell death; decrease of endogenous neurotrophic factors; DNA fragmentation; and many others. In addition, it should be emphasized that not only oxidative stress alone—although a pivotal pathogenic factor in all these disorders—is essential, but newer studies lend support to the notion that APP dysmetabolism is central in AD etiology (APP being an important substance in synaptic and other neuronal compartments), which is supported by many studies (see, among others, Delacourte, In: Recent Progress in AD and PD, Hanin et al., eds, Taylor & Francis, 2005, pp. 301-7).
On the other hand, one can fully support the author’s notion that "SPs [senile plaques] and NFTs [neurofibrillary tangles] are empirical modifications of cellular adaptation," (as are other neuronal protein aggregates, e.g., Lewy and Pick bodies, etc.) as well as the concept that "the long-held notion that pathological lesions in neurodegenerative disorders provide direct insight into etiology, was a fundamental misconception." This concept has been left in recent years, on the understanding that the (semi)quantitative assessment of the two main markers of AD—tau and Aβ —according to current consensus criteria, together with clinical signs of dementia, are only diagnostic "signposts" and are only valuable for the classical "plaque-and-tangle" phenotype of AD, and do not include or consider the other (clinical) and pathological phenotypes of senile dementia. It is important to recognize that pathological diagnosis merely represents the association of a pattern of morphological changes with a clinical phenotype. Therefore, it should be acknowledged that, although Aβ detection and semiquantification of tau pathology have some diagnostic utility, the simple presence of Aβ plaques, as with proteinaceous accumulations in almost all neurodegenerative disorders, do not presume etiology. Therefore, these conclusions by the author also are not essentially new.
Comments
Banner Research Institute
I agree with the main thesis of this paper, that the lesions associated with dementia by Alois Alzheimer 100 years ago are latecomers in the pathophysiology of AD. It has become clear that manifestations of Aβ other than the plaque are major culprits and also that there are other molecules vitally involved in disease pathophysiology.
This paper is a solid confirmation of many previous human autopsy studies that showed there is little correlation between the visible AD lesions and rates of dementia. The feedback relationships among amyloid and NFT pathology and toxic metals in dementia should be included in future investigations. Van Rensburg et al. found that amyloid and aluminum bond to each other to quench each other's oxidative toxicity, which is not surprising, as APP is a copper shuttle. The plaques may be a protective sequestration mechanism for both.
References:
van Rensburg SJ, Daniels WM, Potocnik FC, van Zyl JM, Taljaard JJ, Emsley RA. A new model for the pathophysiology of Alzheimer's disease. Aluminium toxicity is exacerbated by hydrogen peroxide and attenuated by an amyloid protein fragment and melatonin. S Afr Med J. 1997 Sep;87(9):1111-5. PubMed.
Institute of Clinical Neurobiology
This is a critical review emphasizing the pivotal role of oxidative stress in the pathogenesis of AD, based on the frequently published notion of the authors that both Aβ deposition and tau pathology represent the sequelae and not the causes of oxidative stress and oxidative modification of cytoskeletal proteins, leading to tau phosphorylation. It also emphasizes that extensive Aβ deposits are signals not of neurotoxicity per se but of oxidative imbalance and are oxidative stress responses. However, this concept does not take into consideration the multiple other noxious factors known to be active in the complex pathogenic cascade of AD and other neurodegenerative disorders, for example, reduced cerebral energy and glucose metabolism related to disorders of insulin receptor transduction pathways; dysfunction of mitochondria leading to cellular bioenergy crisis; misfolding and accumulation of insoluble proteins—probably as a means to protect cells from toxic protein influences and to delay cell death; decrease of endogenous neurotrophic factors; DNA fragmentation; and many others. In addition, it should be emphasized that not only oxidative stress alone—although a pivotal pathogenic factor in all these disorders—is essential, but newer studies lend support to the notion that APP dysmetabolism is central in AD etiology (APP being an important substance in synaptic and other neuronal compartments), which is supported by many studies (see, among others, Delacourte, In: Recent Progress in AD and PD, Hanin et al., eds, Taylor & Francis, 2005, pp. 301-7).
On the other hand, one can fully support the author’s notion that "SPs [senile plaques] and NFTs [neurofibrillary tangles] are empirical modifications of cellular adaptation," (as are other neuronal protein aggregates, e.g., Lewy and Pick bodies, etc.) as well as the concept that "the long-held notion that pathological lesions in neurodegenerative disorders provide direct insight into etiology, was a fundamental misconception." This concept has been left in recent years, on the understanding that the (semi)quantitative assessment of the two main markers of AD—tau and Aβ —according to current consensus criteria, together with clinical signs of dementia, are only diagnostic "signposts" and are only valuable for the classical "plaque-and-tangle" phenotype of AD, and do not include or consider the other (clinical) and pathological phenotypes of senile dementia. It is important to recognize that pathological diagnosis merely represents the association of a pattern of morphological changes with a clinical phenotype. Therefore, it should be acknowledged that, although Aβ detection and semiquantification of tau pathology have some diagnostic utility, the simple presence of Aβ plaques, as with proteinaceous accumulations in almost all neurodegenerative disorders, do not presume etiology. Therefore, these conclusions by the author also are not essentially new.
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