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Figure 14.4. Processing of amyloid precursor protein (APP) by the secretase enzymes. It would appear that y-secretase is primarily important for the formation of /î-amyloid.

w vi cortex followed by the hippocampus and eventually affect the complete cortex. Such changes reflect the duration and severity of the disease. Figure 14.5 illustrates the role of tau protein in the formation of NFTs in the axon and cell body.

As stated above, the main pathological features of Alzheimer's disease are the amyloid deposits around blood vessels and in many brain areas, intraneuronal neurofibrillary tangles, neuronal cell loss and brain atrophy. Recently four genes have been linked to Alzheimer's disease. Most of the cases of the familial, early onset, form are associated with mutations in genes on chromosomes 1,14 and 21. The late onset and most common form of the disease which occurs in those of 55+ years, whether of the familial or sporadic type, is linked to a gene on chromosome 19.

Advances in the molecular biology of Alzheimer's disease reflect the application of genetics. The identification of the neuropathological changes in Down's syndrome with mutations on chromosome 21, and the mapping of the amyloid precursor protein (APP) gene, led to the discovery of several mutations of the APP gene in patients with Alzheimer's disease. However, it was found that mutations of the APP gene occurred in fewer than 5% of all familial forms of the disease. Subsequently it was found that the majority (70%) of the familial forms were associated with a gene on chromosome 14. This was subsequently found to be the presenilin-1 gene; a locus for the presenilin-2 gene was also found on chromosome 1.

The presenilins code for a seven-membrane protein, similar to G protein coupled receptors, but the precise function of these proteins is unknown. However, it is known that they resemble two proteins found in the nematode Caenorhabditis elegans. This is a microscopic organism containing about 100 neurons and a source of major interest to molecular biologists as it has enabled a functional link to be made between the genetic structure and the biochemical and behavioural changes. It would appear that the presenilin-type proteins in C. elegans play a role in intracellular protein trafficking and may therefore be important in apopotosis (programmed cell death) and in the processing of beta amyloid protein.

The mutation of APP and the presenilins account for most early onset, hereditary Alzheimer's disease. With regard to the common, late onset form of the disease, it appears to be highly associated with the apolipoprotein E4 allele on the long arm of chromosome 19. The cholesterol binding protein ApoE4 is however neither necessary nor adequate to develop Alzheimer's disease, but it does confer a greater risk for the development of the disease. ApoE is localized in senile plaques and binds to beta amyloid protein. This suggests that it is involved in the processing of APP and in the generation of amyloid plaques. The role of ApoE is summarized in Figure 14.6 and Figure 14.7 summarizes the inter-relationship between the various neuropathological changes associated with Alzheimer's disease.

synapse

axonal transport kinases phosphatases

tau stabilizes microtubules (MT)

tau phosphorylation MT depolymerization

PHF (paired-helical filaments) assembly

©CNSforum.com

r1 N

Figure 14.5. Diagrammatic representation of the role of tau protein (a) in the normal axon where it stabilizes the microtubules and (b) in the formation of neurofibrillary tangles (paired helical filaments) in the brain of patients with Alzheimer's disease.

• ApoE binding to amyloid - influencing accumulation,clearance. A aggregation and toxicity of amyloid (dependent on ApoE iiaform)

stabilising microtubuies ^^^jEu1' ^fciA^PP

through the interaction ^^ ^^

Wltti tau (depended on ApoE isoform) inhibit«! by ApoE3

no effect by ApoE4

di rent na urotoxic j affects of ApoE4

©CNSforum.com

Figure 14.6. The role of apolipoprotein (Apo)E4 in the genesis of plaque and neurofibrillary tangle formation. Note that ApoE3 may have a protective effect against the activation of the microglia and the production of pro-inflammatory cytokines (such as interleukin-1).

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