By Steven Brenner
Affiliated with Neurology Departments at the Saint Louis VA Medical Center and Saint Louis University Medical Center.

Posted 19 August 2003

Abstract
White matter abnormalities are characteristic of Alzheimer's disease and are associated with loss of oligodendroglial and astrocytic function. Sulfatide deficiency would result in loss of myelin support for neuronal function. Also, carnosine is not synthesized in sufficient amounts to offer protective function to neurons from oxidation, including divalent metal catalyzed hydroxyl radicals, and b-amyloid-mediated toxicity, carnosine being an antioxidant, metal chelator, and antiglycating agent.

Injury to glia, including oligodendrocytes and astrocytes, may be mediated through hypertension and ApoE epsilon4 allele effects on endothelial vessel walls; metal toxicity from aluminum, which may be toxic to glia; and aging, which is noted to be a prominent risk factor for Alzheimer's disease.

Measures which reduce toxicity to vascular endothelium and glia, such as fish oil, may have potential for reducing the likelihood of development of the disease, while medicines such as some anticonvulsants, which increase carnosine-like substances such as homocarnosine, may be able to reduce the effects of the disease on neuronal structures.

Introduction
Oligodendrocytes and glia contribute carnosine to neurons with consequent protection from oxidation and binding of divalent metals such as copper, iron and zinc.

Oligodendrocytes and astrocyte function is disrupted by various factors including aging, aluminum toxicity, and small vessel disease with white matter stress. Subsequently, oligodendrocytes are not able to synthesize carnosine, and astroglial cells are not able to absorb or receive carnosine from the systemic circulation.

The olfactory ensheathing cells synthesize carnosine (1). Dementia of the Alzheimer's type often is associated with loss of smell at its early stages, indicating there may be early development of pathology in the olfactory system. Involvement of the olfactory bulb and tract is one of the earliest events in degeneration in Alzheimer's disease (2). Carnosine has been found to be taken up effectively by astrocytes but not by oligodendrocytes, while synthesis of carnosine was only observed in oligodendrocyte cultures (3).

Carnosine and carnosine-related dipeptides, besides being highly expressed in the mammalian olfactory neurons, have also been demonstrated in glial and ependymal cells. High carnosine-like immunoreactivity has been seen in rodent subependymal layer, an area which shares with olfactory neuroepithelium the occurrence of continuous neurogenesis during adulthood (4).

Cerebral white matter lesions in Alzheimer's disease consist of subcortical degeneration and ischemic-hypoxic changes. Glial changes are intimately associated with the white matter lesions (5). Regressive changes in astrocytes and glial apoptosis are to some extent associated with white matter lesions, particularly of the temporal lobe in Alzheimer's disease brains.

Astrocytic numbers, astrocyte/oligodendrocyte ratio, and astrocytic reactivity were significantly greater in a demented group of Alzheimer's patients when compared to age matched controls, while oligodendrocytic and total glial counts were significantly lower in demented subjects. Astrocyte/oligodendrocyte ratio is positively correlated with the severity of white matter disease (6).

Alzheimer's disease brains had significantly more white matter hyperintensities on MRI than did controls, and histopathological denudation of the ventricular ependyma and gliosis were significantly more severe in Alzheimer's disease than in controls. The mean thickness of the adventitia of the arteries of the deep white matter in Alzheimer's disease almost doubled the value in control brains; however, there was no evidence of atherosclerosis. Since imaging and histopathologic correlation were similar in Alzheimer's disease patients and controls, the changes probably represented some form of accelerated aging (7).

Sulfatide, which is synthesized primarily in the oligodendrocytes (8) in the CNS, is markedly diminished in patients with Alzheimer's disease pathology—even in patients with very mild dementia—and may be linked with early events in the development of Alzheimer's disease (9).

It is uncertain what leads to the disruption of oligodendrocytes and astrocytes. It may not even be necessary for destruction of the oligodendrocytes and astroglial cells. Aluminum has been noted to impair gap junctional intercellular communication between astroglial cells in vitro. In the CNS, the extracellular environment and metabolic status of neurons are dependent upon astrocytes which are known to exhibit gap junctional intercellular communication. If the cell-to-cell communication with loss of cytoplasmic continuity between adjacent cells is disrupted, exchange of diverse ions, second messengers, and metabolites will not occur (10). This may prevent essential nutrients from reaching the neurons and also cause buildup of metabolic byproducts in neurons, since there may not be a way for them to exit from the cell without closely interrelated glial supporting elements.

Aluminum may cause death of glial cells. Glial cells appeared to be dead in greater numbers when treated with aluminum than in similar cell cultures treated with glutamate in order to investigate cell death from excitotoxicity (11). Initially in my own investigations of aluminum toxicity, I thought this was due to the sensitivity of the technical factors leading to cell death in glial cultures; however, further studies by other investigators have also demonstrated glial toxicity from aluminum. Aluminum induces apoptotic degeneration of astrocytes, and the toxicity to the astrocytes was critical in determining neuronal degeneration and death (12). Aluminum does have age-related accumulation in the brain (13), with levels increased by 28 times in the hippocampus (nondemented non-elderly 14.4+/-1.39 ppb vs. nondemented elderly 401.7+/-60.05 ppb) and 19 times in the frontal lobe (nondemented non-elderly 20.4 +/- 2.54 ppb vs. nondemented elderly 373.29 +/- 72.35 ppb) when comparisons were made between nondemented elderly subjects and nondemented non-elderly subjects. In normal brain tissue, positive Morin fluorescence reaction indicating the presence of aluminum was observed in the wall of the capillary vessels of the blood-brain barrier, perivascular glial supporting tissues, the nuclei of the astrocytes, and nuclei and nucleoli of the nerve cells, partially. Histochemical demonstration of aluminum localization by Morin method also showed a positive fluorescence reaction along the sites of neurofibrillary tangles and amyloid core in senile plaques of nondemented elderly subjects.

Mutations in the gene encoding presenilin-1 cause some cases of early-onset inherited Alzheimer's disease. Oligodendrocytes from presenilin-1 mutant knockin mice are more vulnerable to being killed by glutamate and amyloid b-peptide, and exhibit an abnormality in calcium regulation which causes their death. The findings in the presenilin-1 knockin mice suggest a mechanism responsible for white matter damage in Alzheimer's disease and the effect of such damage on cognitive impairment (14).

If oligodendrocyte function is disrupted, carnosine contribution to neurons will not be available to protect neurons from metal-induced oxidation reactions, since carnosine is capable of scavenging different radicals and binding divalent metal ions such as iron, zinc, and copper (15). It is believed Ab precipitation and toxicity in Alzheimer's disease are caused by abnormal interactions with neocortical metal ions, especially Zn, Cu, and Fe (16). Studies on redox-competent copper and iron indicated redox activity in Alzheimer's disease was located within the cytosol of vulnerable neurons, and that oxidative damage in Alzheimer's disease is due to production of metal-catalyzed hydroxyl radicals that damage every category of macromolecule (17). Mitochondria also may be a potential source of redox-active metals and oxygen radical production (17).

There does appear to be an age-related trend in the intensity of carnosinase immunoreactivity in the olfactory mucosae of older subjects (18), which may indicate an age-related decline in the production of carnosine. Decreased carnosine availability would probably indicate a greater vulnerability of the brain to oxidative and free radical stress.

Carnosine also prevented toxic effects of b-amyloid peptide (25-35) on rat brain vascular endothelial cells in cell culture (19), which may indicate a protective effect from the b-amyloid peptide believed to be toxic in Alzheimer's disease. Carnosine prevented cell damage completely at 200 mg/ml A b and partially at 300 mg/ml A b. Similar agents such as b-alanine, homocarnosine, and the antioxidant superoxide dismutase also partially rescued cells, as well as the antiglycating agent aminoguanidine. It appeared the mechanism of carnosine protection was in its antiglycating and antioxidant activities. Formation of Advanced Glycation End-products (AGE) amyloid peptide aggregates could be attenuated by AGE-inhibitors such as Tenilsetam, aminoguanidine, and carnosine(20). Nucleation-dependent polymerization of b-amyloid peptide, the major component of plaques in patients with Alzheimer's disease, is accelerated by crosslinking through AGEs in vitro. Both nucleus formation and aggregate growth are accelerated by AGE-mediated crosslinking.

Conclusion
White matter changes involving oligodendrocytes and astrocytes are prominent in Alzheimer's disease. White matter changes observed on MRI testing, as well as pathological change in oligodendrocytes and deficiency in sulfatide, a product primarily of oligodendrocyte synthesis, are characteristic of Alzheimer's disease.

Disruption of oligodendrocyte and astrocytic function also may lead to a deficiency of carnosine production as well as of related dipeptides which have antioxidant and free radical scavenging function. Carnosine and related dipeptides also inhibit AGE with inhibition of b-amyloid aggregation, and also appear to be protective against b-amyloid toxicity. Carnosine is also believed to have binding effects on divalent metals such as zinc, copper, and iron, which are involved in the oxidative reactions of Alzheimer's disease.

Disruption of white matter (oligodendrocytes and astrocytes) may have various contributing factors such as vascular dysfunction from hypertension, aluminum toxicity, aging, and presenilin-1 mutation. The ApoE epsilon4 allele favors vascular over parenchymal accumulation of A b in Alzheimer's disease (21), and may contribute to vascular disease causing white matter changes in Alzheimer's disease.

Anticonvulsants such as topiramate (22) and vigabatrin (23) increase the amounts of homocarnosine (a dipeptide of g-aminobutyric acid and histidine) in brain, and could have potential for replacing the deficiency of carnosine which may develop during the course of Alzheimer's disease. Seizures occasionally occur during the course of Alzheimer's disease, so anticonvulsants are commonly utilized in such situations. Anticonvulsants which increase homocarnosine and protective substances in the brain may have potential beyond just treatment of epileptic seizures.

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