Pathology

Microscopically the brains of AzD patients often show neuronal loss and some atrophy, much as in Down Syndrome, as well as widened sulci and narrowed gyri. Since,

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Figure 18.1 Typical tangle (T) and plaque (P) as visualised by silver impregnation in the cerebral cortex of a case of Alzheimer's disease. The extracellular plaque (10-50 p.m diameter) consists of a central core of amyloid surrounded by glial processes and a number of neurites in a ring formation. The intracellular cytoplasmic tangle is composed of helical filaments in a paired format. (Reproduced with permission of Academic Press from Wischik and Crowther 1986)

Figure 18.1 Typical tangle (T) and plaque (P) as visualised by silver impregnation in the cerebral cortex of a case of Alzheimer's disease. The extracellular plaque (10-50 p.m diameter) consists of a central core of amyloid surrounded by glial processes and a number of neurites in a ring formation. The intracellular cytoplasmic tangle is composed of helical filaments in a paired format. (Reproduced with permission of Academic Press from Wischik and Crowther 1986)

however, such changes are not uncommon in elderly people (75+) these features can only really be considered indicators of the disease when found in younger patients. This does not apply to the plaques and tangles.

SENILE PLAQUES

Appropriate silver staining and immunohistochemical localisation of ^-amyloid show these to be extracellular lesions which in their typical neurite form are roughly spherical in shape (10-50 ^ diameter) with a central core of amyloid surrounded by glial processes and a rim of neurites. The amyloid can sometimes exist alone (compact plaque), when the neurites no longer react to silver staining or in a diffuse state (primary plaque) before neurites have formed. It is unclear whether the development of neuritic from diffuse plaques causes neurofibrillary pathology and neuronal dysfunction or results from those processes. Plaques are, however, indices of neuronal death, generally of large pyramidal cells. They are found mostly in the cerebral cortex, especially the hippocampus and frontal temporal area, and while most common in AzD brain they also occur in Down Syndrome and in pugilistic (brain damage) dementia and can even be found sparsely in the normal ageing brain.

NEUROFIBRILLARY TANGLES

These are intraneuronal cytoplasmic lesions found predominantly in large pyramidal cells, again, mostly within the hippocampus and frontal temperal cortex, and while they can be seen in some other conditions, e.g. post-encephalatic Parkinsonism and Down Syndrome, they are generally considered to be more specific to AzD than the plaques. The tangles are composed of tau® protein, which normally promotes polymerisation of the microtubules that maintain cell structure, but for some reason has become hyperphosphorylated and deposited as helical filaments in a characteristic entwined paired format which disrupts neuron function. Hirano bodies, which are intraneuronal eosinophile inclusions, are also seen in AzD.

FORMATION OF ^-AMYLOID AND ITS EFFECTS

Most cases of AzD show cerebrovascular amyloid deposits and the amyloid protein of senile plaques is the same as that found in blood vessels. It is referred to as [-amyloid protein and is part of a 695, 751 or 770 amino-acid amyloid precursor protein APP, which is a transmembrane protein and although its precise function is not clear, it is widely distributed and APP knock-out mice show reduced motor function. Normally so-called short 40 amino-acid-soluble derivatives of APP are produced by proteolytic cleavage of APP within the [ (A4) amino-acid sequence but APP can also be cleaved

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Figure 18.2 Production of senile plaque [/A4 amyloid protein. Amyloid [64 protein ([/A4) is part of a 695, 751 or 770 amino-acid amyloid precursor protein APP. This is a transmembrane protein which is normally cleared within the [/A4 amino acid sequence to give short 40 amino-acid soluble derivatives. It seems that under some circumstances as in Alzheimer's disease, APP is cleared either side of the [/A4 sequence to release the 42/43 amino acid [/A4 which aggregates into the amyloid fibrils of a senile plaque (a). (See also Fig. 18.5.) Some factors, e.g. gene mutation, must stimulate this abnormal clearage leading to the deposition of [/A4 amyloid protein as plaques and tangles and the death of neurons (b)

Figure 18.2 Production of senile plaque [/A4 amyloid protein. Amyloid [64 protein ([/A4) is part of a 695, 751 or 770 amino-acid amyloid precursor protein APP. This is a transmembrane protein which is normally cleared within the [/A4 amino acid sequence to give short 40 amino-acid soluble derivatives. It seems that under some circumstances as in Alzheimer's disease, APP is cleared either side of the [/A4 sequence to release the 42/43 amino acid [/A4 which aggregates into the amyloid fibrils of a senile plaque (a). (See also Fig. 18.5.) Some factors, e.g. gene mutation, must stimulate this abnormal clearage leading to the deposition of [/A4 amyloid protein as plaques and tangles and the death of neurons (b)

either side of the 6 sequence to liberate the longer 42 (or 43) amino-acid-insoluble ¿-amyloid protein (Fig. 18.2). One possibility is that in AzD this process is excessive and the insoluble amyloid 6 protein (A6) aggregates to form the amyloid fibrils and core of the senile plaques. The protein may also stimulate the phosphorylation of tau and the production of neurofibrillary tangles. How it kills neurons is unclear. Suggestions include the production of free radicals, sensitisation to glutamate and increased Ca2+ influx. The last has been shown in in vitro studies but these tend to use concentrations in excess of those found in the brain and often with shorter and soluble synthetic forms of A6. Certainly the direct injection of ¿-amyloid or neurotic plaques into rat brain does not appear to kill neurons but continuous infusion of A6 (1-40) into the cerebral ventricles of rats does lead to impairment of learning and memory (Nitta et al. 1997).

In fact no consistent correlation has been found between the appearance, distribution and number of amyloid plaques and either neuronal loss or the degree of dementia, although the latter correlates with the number of neurofibrillary tangles, which tend to precede plaques in appearance by some years. Also cortical amyloid deposits can be found in non-demented elderly patients. Thus the basic question appears to be: does the disease process, whatever that is, cause the development of AzD as well as the production of ¿-amyloid or is there production of ¿-amyloid, which then causes AzD? Consensus supports the latter but it is not proven.

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