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Renato Cocchi M.D., Ph.D. (Sociology); Giovanni Somenzini, M.D.; Francesco Zerbi, M.D. Italian Journal of Intellective Impairment 1 (2): 127-132 (1988) Fondazione Mondino - Clinica Neurologica dell'Università di Pavia Centro di Neuropsichiatrìa Biologica Paper presented at the 1st Congress of the Eur. Neurol. Society, Nice, June 1988 |
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Reprinted with the permission of Renato Cocchi Via A. Rabbeno, 3 42100 Reggio Emilia, Italy +39 0522 320 716 Mobile +39 348 5145 520 URL: http://www.stress-cocchi.net |
The reduced inactivation of oxygen's free radicals is one of the hypotheses put forward to account for the onset of Alzheimer's dementia. However scarce conclusive experimental data may be to support this theory regarding human species, its refutation has not been established with any certainty either. Subjects affected by Down's syndrome have a documented increase in the enzyme superoxide-dismutase-1 and about 30% increase in the enzyme glutathione-peroxidase, both scavengers of oxygen's free radicals.
For this reason Down subjects, who are less prone to cerebral palsy from prematurity and low birthweight (Cocchi, 1987; Cocchi and Branchesi, 1988), should also show a retardation in the onset of dementia, compared to normal individuals. This is not however the case as on the contrary it is regularly found that Down subjects anticipate by an average of 15 years roughly the onset of an Alzheimer type of dementia. Key words: Alzheimer type dementia; etiology; free radicals; Down subjects.
The metabolic use of oxygen, by organic tissues in mammals, provokes normally an initial production of the radical anion superoxide (O2·) which, if in excess, can alone damage the cellular DNA, oxidize the thiolic groups of the proteins and cause other toxic events such as lipidic peroxidation [1-2]. Anion superoxide is usually inactivated by its transformation into hydrogen peroxide (H2O2).
This transformation comes about through two metabolic reactions. First, the divalent reduction of O2·, catalysed by enzymes such as urate- and D-amino-oxidase; and second by spontaneous or enzymatic dismutation in the presence of the enzyme superoxide-dismutase (SOD) [3-4]. Hydrogen peroxide has been alleged to produce cytotoxicity [5], but this is a debatable result in vivo, and it is possible that cellular toxic effects are rather due to the formation of other reactive compounds.
Hydrogen peroxide normally becomes inactivated by at least two protective enzynatic mechanisms: Either reduced to H2 + O2, by the catalase of the intercellular peroxisomes, or again reduced to H2O, this time by means of glutathione-peroxidase (GSHPx) [3-4].
lf for any reason, usually contingent and acute, and prevalently anoxic-ischaemic [6-10], this inactivation system becomes inadequate, either the combination of anion superoxide and hydrogen peroxide derived from the dismutation, or Fenton-type reactions by the hydrogen peroxide in the presence of copper or iron salts can produce the hydroxilic radical (OH·) which is extremely reactive with, in effect, any type of organic molecule, so as to cause irreversible cellular damage [3-4].
One theory on ageing attaches great importance to continuous and chronic cellular damage produced by oxygen free radicals [11-14], and tends to support this point of view by the report of lipofuscins build up, brought about by decay of the cellular membranes. This build up depends on oxygen and is age-related [5; 15-18].
In actual fact the autooxidation of polyunsaturated fatty acids is a metabolic process which is able to form malondialdehyde and free radicals, both of which can react with essential cell components to give lipofuscins as a product of decay [15-16]. Furthermore, free radicals can also directly damage the genes [1]. Although, through the intervention of special enzymes, the cell tends to repair the damage done to DNA, the capacity to do so is strongest only in the mitotic phase [19].
The free radicals can be formed by the oxidation of the cellular membranes of the cells belonging to the CNS, which are highly sensitive to their toxic action, due to the fact that these are cells which do not reproduce themselves and lie in the post-mitotic stage, when the activity is at its lowest [19-20].
The accumulation of lipofuscins, which takes place particularly in the mitochondria, is a process brought on by ageing and is not specific to Alzheimer's disease [21]. However much aldehydes and ketones produced by the action of free radicals play their part in the beginning of this process, in actual fact the formation of lipofuscins in an individual is a metabolic chain not yet fully understood [16]. It seems that malondialdehyde has a role in the formation of proteins and lipids, constituents of lipofuscins[16].
On the other hand, CNS neurons also possess catalase, glutathione-peroxidase and superoxide-dismutase, being the scavengers against the action of the free radicals [16].
However interesting the hypothesis may be that the cytotoxic action of free radicals is the cause of dementia, it is based on questionable premises. Even though oxygen's free radicals are cytotoxic and can eventually lead to a build up of lipofuscins and although dementia and the accumulation of lipofuscins are two age-related processes, this does not necessarily mean, and it has yet to be demonstrated, that dementia is caused by the accumulation of lipofuscins.
It is quite true that a whole series of illnesses presenting an accumulation of lipofuscins (from neural ceroid lipofuscinoses to vitamin E deficiency and the effects of certain chronic intoxications) are also accompanied by mental deterioration [16] but this is something common to all pathological thesaurismoses. It is sure however that in Alzheimer's disease, the most common form of dementia, an accumulation of lipofuscins in the mitochondria is present, but the same is true for non-demential ageing [21].
Research has been carried out to support this hypothesis. No difference has been found between normal individuals and those with Alzheimer's type of dementia, regarding the activity of their brain SOD [22]. Taking the erythrocyte as a model, outside of the CNS of a nerve cell, the erythrocytal activity of the SOD and GSHPx in patients affected by multi-infarctual dementia and Alzheimer's dementia has not been found to be different [23].
No significant differences in blood levels of 12 vitamins were found in a group of Alzheimer's disease patients and a control group of healthy, depressed or other-type-demented subjects [24]. It should also be pointed out that neuropathological examination of cerebral lesions in a patient with generalized glutathione deficiency, due to defective synthesis of glutathione (which might impair the cells antioxidant ability) revealed only selective atrophy of cells of the granular layer of the cerebellum and patchy loss of neurons in a laminar pattern of the visual cortex.
No changes suggestive of senile dementia were noted [25]. In addition to intravenous injections of liposome-entrapped catalase and superoxide dismutase against oxygen toxicity outside the CNS [26-27], intravenous injections of liposome-entrapped superoxide dismutase has also protective effects on post-traumatic brain edema [28].
There is however one important natural experiment which is able to question the hypothesis of the cytotoxic action of oxygen's free radicals as being the cause of dementia. It is well known that Down subjects anticipate by an average of 10-15 years a form of dementia which is not distinguishable, either from a neuropathological point of view or a behavioural one, from Alzheimer's disease [29].
Furthermore, such a dementia is much more common in Downs than in the normal subjects, and affects over 40% of those who live beyond the age of 50 years [30]. It is interesting to note though that in Down subjects 50% increase is found in the enzymatic activity of the SOD-1, the control gene of which is allocated in chromosome 21, tripled in these individuals [31-35].
As well as this, an adaptive increase of 30% has been revealed in the enzymatic activity of the GSHPx [35-38]. The increased presence of these two scavengers seems to be responsible for the reduced incidence of CP from prematurity and low birthwight [39-40], the main risk factors for it.
These two conditions are quite frequent also in Down newborns [39-40] and usually can lead to cerebral lesions by means of anoxic-ischemic mechanisms. Being more able to inactivate the oxygen's free radicals, the Down individuals should also therefore be protected from dementia, if this is due to the action of the free radicals.
The fact that this is not the case, but on the contrary, there is an anticipation and increase in the onset of demential evolutions, must be taken as a high probability disproval of the theory that advances the chronic toxic action of the free radicals as the cause of Alzheimer's disease, at least for Down subjects.
As regards normal individuals there should not be any difference, but being rather over-cautious we intend the above explanation to be taken only as a strong indication and as further confirmation of the experiments which we have cited [22-28].
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