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FIGURE 6.17 Hypothesis for development of Alzheimer's disease. P and y secretases sequentially cleave the cytoplasmic domain of the amyloid precursor protein (APP) to yield P-APP and amyloidp (AP). AP leads to neurodegeneration through multiple pathways, including the formation of plaques and neurofibrillary tangles. Reproduced with permission from Cummings, Alzheimer's disease. New Eng J Med 351:56-67. Copyright 2004, Massachusetts Medical Society.

FIGURE 6.17 Hypothesis for development of Alzheimer's disease. P and y secretases sequentially cleave the cytoplasmic domain of the amyloid precursor protein (APP) to yield P-APP and amyloidp (AP). AP leads to neurodegeneration through multiple pathways, including the formation of plaques and neurofibrillary tangles. Reproduced with permission from Cummings, Alzheimer's disease. New Eng J Med 351:56-67. Copyright 2004, Massachusetts Medical Society.

4. Alzheimer's Disease

Alzheimer's disease places one of the highest economic and social burdens on caregivers of any neurodegenerative disease. The incidence of Alzheimer's increases to 30%-40% in persons over the age of 85 and has an economic impact of $80-$100 B/year

(Mattson, 2004). The causes of the disease are believed to be both genetic and environmental. Proteolytic processing of ß-amyloid precursor protein into amyloid-ß peptides, and hyperphosphorylation of the micro-tubule-associated tau protein lead to the plaques and neurofibrillary tangles that characterize Alzheimer's (figure 6.17). Initial symptoms of Alzheimer's are subtle, but as the disease advances, there is clear-cut progressive loss of memory and cognition until the persona is destroyed and all control over physical function is lost (Cummings, 2004).

Various rat models of Alzheimer's are available for experimentation. Cells from a variety of cholinergic tissues (fetal basal forebrain, nodosal ganglion, intra-cortical adrenal chromaffin cells, and chemically differentiated neuroblastoma cell lines) survived when injected ectopically into the terminal areas of the fore-brain cholinergic projection system of these models, and significantly reversed deficits in cognitive behavior (Hodges et al., 1991, a, b, c). These transplants contained both neurons and glial cells. Transplants of non-cholinergic cells from the hippocampus had no effect. If glial cells and neurons from cholinergic areas were transplanted separately, the glial cells promoted the recovery of cognitive function, but the cholinergic neurons did not (Bruckner and Arendt, 1992; Sinden et al., 1995). Thus, when cells from a cholinergic area were transplanted, the glial cells of this tissue may have been increasing acetylcholine (Ach) secretion by host cholinergic neurons, as well as fostering axonal outgrowth and Ach secretion by donor cholinergic neurons. These results suggest that the transplanted cells secrete paracrine factors that exert a neuroprotective effect on host neurons, opening the possibility for pharmaceutical treatments that can halt the disease and permit the regeneration of new neurons from resident NSCs.

Pharmaceutical companies are testing more than two-dozen experimental treatments for Alzheimer's. Among these are several drugs that may control or reduce symptoms of Alzheimer's, although none can halt its progression (Cummings, 2004; Pallarito, 2004). Cholinesterase-inhibiting drugs, which work by slowing the rate of breakdown of Ach, are Aricept (donepezil), Exelon (rivastigmine), and Reminyl (galantamine). According to the Alzheimer's Association, these drugs slow cognitive decline in at least half of patients who have mild cognitive impairment. Namenda (meman-tine) is a new drug that is thought to work by protecting brain cells from excess glutamate. Two drugs, Alzhemed and Clioquinol (PBT-1), target the aggregation of P amyloid peptides into plaques. A small Phase II trial of Clioquinol indicated that it was able to reduce the rate of decline of cognitive function in patients with moderate to severe Alzheimer's (Ritchie et al., 2003). Still another drug in Phase III trials is Axonyx, which can inhibit both cholinesterases and prevent plaque formation.

One of the problems with drugs directed at inhibiting plaque formation is that they are too small to effectively block the interaction between P-amyloid peptides. A new strategy to prevent the aggregation of P-amyloid peptides is to sterically "bulk up" a small bifunctional molecule that binds on one end to P-amyloid peptide and on the other end to a large molecule that also sticks to P-amyloid peptide. Gestwicki et al. (2004) made such a small molecule by coupling the dye Congo Red (CR) to a synthetic ligand (FKBPL) that binds to the FK506 binding protein (FKBP) chaperone family of peptidyl prolyl cis-trans isomerases (figure 6.18). When added to P-amyloid along with FKBP, the CR-FKBPL molecule delayed or completely prevented aggregation of P-amyloid in test-tube assays and prevented neuronal cell death in vitro caused by P-amyloid added to the medium. CR, however, does not enter cells (where the P-amyloid is being produced), so an alternative to CR needs to be found before this approach can be developed into a clinical drug (Wickelgren, 2004). These results suggest that aggregates of P-amyloid peptides are neurotoxic.

Provision of an enriched environment (including exercise) to mice suffering from a familial form of AD (Lazarov et al., 2002) reduces the levels of P-amyloid peptides and amyloid deposition in the hippocampus and cortex (Lazarov et al., 2005). They showed by microarray analysis that a number of genes involved with learning and memory, vasculogenesis, neurogene-sis, cell survival pathways, amyloid-P sequestration, and prostaglandin synthesis were upregulated in the hippocampus of enriched mice. Neprilysin (NEP), an enzyme that degrades amyloid, was significantly elevated, suggesting enhanced clearing activity. These results are consistent with previous results demonstrating the effects of enrichment and exercise on learning and memory in young and old mice (Chapter 5), the effects of physical therapy regimens on spinal cord injury, and in the delay of onset of neurological signs in Huntington's disease. Although many questions remain about the degree to which environmental enrichment for mice corresponds to the exercise of mental capabilities in humans, and what may be cause or effect, Karsten and Geschwind (2005) point out that other work shows that higher degrees of educational attainment, exercise, occupational status and a strong social network all have positive effects on maintaining cognitive powers with age.

5. Amyotrophic Lateral Sclerosis

ALS is a progressive, fatal disease characterized by the death of spinal cord large motor neurons. The cause of the disease is unknown, but may include genetic susceptibility, cellular aging, and as yet unidentified environmental factors (Rowland and Scheider, 2001). Ninety to ninety-five percent of all cases are sporadic.

Regenerative Medicine of Neural Tissues

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