Introduction
Amyloid b protein, amyloid protein precursor and Alzheimer's disease
ApoE, Presenilin 1, 2 and Alzheimer's disease
Prospects
Literature References

Introduction
Alzheimer's disease (AD) is a disease that causes deficits in memory and learning and is the major cause of cognitive deterioration in the elderly. Throughout the world, approximately 10% of people in their 70s and 30% in their 80s suffer from Alzheimer's disease. Its symptoms include forgetfulness, estrangement of the family members and friends, depression, loss of homing instinct and time sensitivity. AD has two neuropathological hallmarks: extracellular formation known as senile plaques (SP, a dense heterogeneous extracellular deposit) and intracellular silver-stained formations called neurofibrillary tangles (NFT). Filamentous brain lesions could occur within neurons (neurofibrillary tangles), in extracellular cerebral (amyloid plaques), and in meningocerebral blood vessels (amyloid angiopathy).^{1, 2}

Amyloid b protein, amyloid protein precursor and Alzheimer's disease
Amyloid b protein (Ab) has been identified as a 4 kDa hydrophobic non-glycosylated peptide consisting of 39-43 amino acid residues and derived from a 700 amino acid residue of a membrane-associated glycoprotein, the amyloid precursor protein (APP) by specific endoproteolytic cleavages.2,3 Ab appears in bundles of amyloid fibrils surrounded by abnormal neurites and is believed to be the major subunit of the vascular and plaque filaments in individuals with Alzheimer's disease, elderly people, and patients with trisomy 21 (Down's Syndrome). In vitro studies recently indicated that synthetic Ab1-42 could form insoluble aggregates and produce neurotoxicity after incubation for several days.1 The Ab1-42 assemblies are positive in Congo red and thioflavine S staining similar to that observed in AD brain. The synthetic peptide Ab1-40 was found to enhance the aggregation of Ab and exhibit neurotoxic effect in vitro.4 More interesting, peptide Ab25-35 showed strong self-aggregation activity and reproduced both the neurotoxic and the neurotrophic effect in tissue culture, indicating that this portion of Ab may be responsible for biological effects of Ab.1 The aggregation state of Ab seems to play a critical role in developing AD: as Ab is aged, it spontaneously aggregates and self-assembles into higher-order structure. This conformation change transforms Ab into a stimulus which initiates neuronal cell death.⁵

Amyloid protein precursor (APP), encoded by a gene on human chromosome 21, serves as an integral transmembrane cell-surface receptor. It binds and inhibits a number of factors in plasma and proposed to act as a signal for membrane extension. APP missense mutations have been studied in vitro transfection system and are found to increase Ab secretion, particularly Ab1-42.6 Furthermore, plasma Ab level significantly increased in some APP mutation carries. As a result, it is believed that APP mutations cause AD by enhancing cleavages to generate more Ab, thereby promoting the amyloidogenesis.⁷

ApoE, Presenilin 1, 2 and Alzheimer's disease
Inheritance of one or two apoE4 alleles increases risk factor for familial and sporadic AD. AD patients carrying apoE4 show a significant increase in the density of Ab deposit compared to patients carrying no apoE4 alleles. In vitro studies have indicated that ApoE4 can promote amyloid fibril formation by Ab and binding of human apoE4 to synthetic Ab peptide has been identified. Precisely how apoE4 enhances Ab aggregation is still under intensive investigation.7 Presenilin (PS) 1 and 2 belong to highly homologous, multitransmembrane proteins. To date, more than 30 mutations in PS1 and PS2 have been identified. It was found that Ab42 secretion increases after transfection of mutant PS cDNA into cultured peripheral cells. Transgenic mice expressing mutant PS1 also show increased Ab42 levels in the brain. Finally, direct analysis of the brains of patients bearing PS1 mutations demonstrated a significant increase in the density of Ab42-containing plaques compared to that found in patients with sporadic AD.^{6, 7, 8}

Prospects
Current therapeutic strategies for Alzheimer's disease involve decreasing the rate at which patients decline. In the course of AD, patients' cholinergic neurons that produce acetylcholine are lost in the brain. An obvious therapeutic approach is to attempt to enhance the activity of the remaining acetylcholine. The existence of amyloid b protein also provides attractive target for drug discovery. At least four broad classes of AD drugs can now be envisioned: (I) protease inhibitors: that decrease the activities of the enzyme which cleave Ab from APP; (II) compounds that bind to extracellular Ab and prevent its aggregation into cytotoxic amyloid fibrils; (III) brain specific anti-inflammatory drugs that block the microglial activation, cytokine release and acute-phase response that occur in affected brain region; (IV) compounds such as antioxidants, neuronal calcium channel blockers, or antiapoptotic agents that interfere with the mechanisms of Abb-triggered neurotoxicity. Recently, many AD research laboratories have been involved in developing the animal model that might provide insights into the pathology and phenotype characteristics of Alzheimer's disease.

Literature References

1. G. Forloni, F. Tagliavini, O. Bugiani and M. Salmona. Amyloid in Alzheimer's Disease and Prion-Related Encephalopathies: Studies with Synthetic Peptides. Progress in Neurobiology. 49:287-315, 1996
2. D.W. Dickson. The Pathogenesis of Senile Plaques, Journal of Neuropathology and Experimental Neurology. 56:321-339, 1997
3. M. Citron, TS. Diehl, G. Gordon, AL. Biere, P. Seubert, DJ. Selkoe. Evidence that the 42- and 43-amino acid forms of amyloid beta protein are generated from the beta-amyloid precursor protein by different protease activities. Proc. Natl. Acad. Sci. USA, 93:13170-13175, 1997
4. JT. Jarrett, PT. Lansbury. Seeding "noe-dimensional crystallization" of amyloid: a pathogenic mechanism in Alzheimer's disease and scrapie? Cell, 73: 1055-1058, 1993
5. C.W. Cotman. The ß-Amyloid Peptide, Peptide Self-Assembly, and the Emergence of Biological Activities. Annals New York Academy of Sciences. 814:1-16, 1997
6. J. Hardy. Amyloid, the presenilins and Alzheimer's disease, Trends Neuroscience, 20:154-159, 1997
7. D.J. Selkoe. Alzheimer's Disease: Genotypes, Phenotype, and Treatments. Science. 275:630-631, 1997
8. J. Hardy. The Alzheimer Family of Disease: Many Etiologies and Pathogenesis? Proc. Natl. Acad. Sci. USA, 94:2095-2097, 1997
   

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