Attenuation Of Degeneration

Even if NT manipulation had provided an effective therapy in AzD it would still be important to stop the progression of degeneration and the disease process itself. The failure of the NT approach makes it even more vital.

¿-AMYLOID

While the precise cause of AzD remains unknown, the evidence implicating ¿-amyloid is such as to justify attempts to reduce its involvement. The activity of ¿-amyloid might be reduced by:

(a) stopping its production by reducing the phosphorylation and proteolysis of APP

(b) increasing its breakdown

(c) counteracting its toxic effects through plaque formation

APP is normally cleaved within the A¿ sequence by an unidentified protease, so-called a-secretase, so that most of the extracellular APP is released in a soluble form into the extracellular fluid (see Checler 1995). When ¿-amyloid is formed another protease (¿) splits APP so that the complete A¿ sequence persists at the extracellular end of the remaining membrane and intracellular APP chain. This is then cleaved by anaother protease (y-secretase) to release the ¿-amyloid (Fig. 18.5). Potentiation of a-or blockage of ¿- and y-secretase could reduce the production of A¿ which becomes insoluble and is precipitated (see Hardy 1997).

Figure 18.5 Schematic representation of possible cleavage sites of APP by a, fi and y-secretase and the production of fi-amyloid protein. (I) This shows the disposition of APP molecules in 695, 751 and 770 amino-acid chain lengths. Much of it is extracellular. The fi-amyloid (Afi4) sequence is partly extracellular and partly in the membrane. (II) An enlargement of the fi-amyloid sequence. (III) Normal cleavage of APP by a-secretase occurs in the centre of Afi4 sequence to release the extracellular APP while the remaining membrane and intracellular chain is broken down by y-secretase to give two short proteins that are quickly broken down. (IV) In Alzheimer's disease fi rather than a-secretase activity splits off the extracellular APP to leave the full Afi4 sequence remaining attached to the residual membrane and intracellular chain. 42/43 amino acid fi-amyloid sequence is then split off by y-secretase activity

Figure 18.5 Schematic representation of possible cleavage sites of APP by a, fi and y-secretase and the production of fi-amyloid protein. (I) This shows the disposition of APP molecules in 695, 751 and 770 amino-acid chain lengths. Much of it is extracellular. The fi-amyloid (Afi4) sequence is partly extracellular and partly in the membrane. (II) An enlargement of the fi-amyloid sequence. (III) Normal cleavage of APP by a-secretase occurs in the centre of Afi4 sequence to release the extracellular APP while the remaining membrane and intracellular chain is broken down by y-secretase to give two short proteins that are quickly broken down. (IV) In Alzheimer's disease fi rather than a-secretase activity splits off the extracellular APP to leave the full Afi4 sequence remaining attached to the residual membrane and intracellular chain. 42/43 amino acid fi-amyloid sequence is then split off by y-secretase activity

These must be worthwhile objectives and the recent identification by a number of research groups (see Skovronsky and Lee 2000 for description and details) of ¿6-secretase as the membrane-bound aspartyl protease (BACE), ¿-site APP cleaving enzyme, paves the way for developing possible chemical inhibitors of its activity for experimental and clinical evaluation, although that remains for the future.

NEUROTROPHIC FACTORS

Whether or not the production of ¿-amyloid can be curtailed, it would be desirable to either replace the damaged neurons or encourage the remaining functional ones to ramify further and exhibit more influence. The former, which requires tissue or cell line grafts, is currently not feasible and barely investigated experimentally but there is much interest in the possible use of neurotrophic proteins (neurotrophins) that encourage neuronal growth and differentiation.

A number of these have been isolated and identified but the first to be discovered (see Levi-Montalcini 1987), and the most studied, is nerve growth factor (NGF) which, despite its name, is not universally effective on all neurons. In the periphery it is mainly released in tissues containing sympathetic nerves that take it up and transport it retrogradely to the cell body where it acts. In the brain, however, it has more influence on cholinergic than noradrenergic or other neurons so that NGF protein and MRNA expression is highest in cholinergic innervated areas of the brain such as the hippocampus and cortex while its binding sites (receptors) are mainly in subcortical regions with cholinergic neurons like the nucleus basalis. In fact injection of NGF into the latter's projection areas like the hippocampus and cortex result in its uptake and transport back to the nucleus. So it may be assumed that normally the cortically produced NGF is transported back to cholinergic subcortical neurons where it exerts its trophic action. Certainly NGF increases ChAT production when added to cultured cholinergic neurons and its intraventricular infusion in rats and primates prevents the loss of ChAT activity in and degeneration of, cholinergic neurons caused by transection of the septal hippocampal cholinergic pathway, or ibotenic acid injection into the nucleus basalis. Intraventricular NGF has also been shown to improve learning and memory in aged rats and those with lesions to cholinergic pathways. So if NGF is so important for the growth and function of the cholinergic neurons, that appear so vulnerable in AzD, can they be restored and AzD controlled by administering NGF? Before that question can be answered some practical problems have to be overcome, namely how to obtain and administer it.

If immune reactions are to be avoided then recombinant human factor should be used and that cannot be produced in large quantities. In any case, it is a large protein that will have to be injected directly into the brain. Even if these problems can be overcome the spread and intensity of any NGF effect has to be restricted so that excessive neuritic growth and inappropriate increases in synaptic connections do not occur.

In addition to these problems there is no evidence of reduced NGF in AzD although levels and receptor number are lower in the nucleus basalis. In fact the levels of NGF were found to be increased in the cortex and hippocampus (Scott et al. 1995) and while this could just be due to fewer cholinergic fibres to transport it away from the cortex it does suggest its synthesis is normal and possibly even increased. At least it throws doubt on the value of augmenting NGF as a therapy for AzD.

Nevertheless NGF from mouse mandibular gland has been infused into the right lateral ventricle of two patients (67 and 57 years) for three months at a rate of 75 ^/h. The younger showed no change in memory performance; the older some improvement after one month, which ceased after the infusion was stopped. Both patients had various reversible side-effects such as back pain and weight loss.

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