Introduction
The β-amyloid precursor protein (APP) is connected to Alzheimer's disease by both biochemistry and genetics. As the source of the major constituent of amyloid plaques, APP has been the subject of many studies of its expression and metabolism. The accumulation of amyloid β-peptide (Aβ) in these plaques was the first evidence that APP might be processed abnormally in Alzheimer's, and this idea was strengthened by the discovery of mutations in APP that segregate with the disease with high penetrance. Aberrant processing of APP was incorporated into the Amyloid Hypothesis, which supposes that the clinical symptoms, neuropathology, and ultimate fatality of Alzheimer's result from the actions of Aβ. But to the extent that the Amyloid Hypothesis remains hypothetical, it would be irresponsible to ignore other theories that might explain the links between APP and Alzheimer's. APP can be proteolytically processed in a way that does not produce (and, in fact, precludes) Aβ. This "α-secretase" event cleaves within the Aβ sequence and liberates most of the extracellular portion (sAPPα) of APP from the cell surface. Because the "β-secretase" event required for the generation of Aβ creates a different soluble derivative (sAPPβ), disease-related increases in β-secretase processing-such as demonstrated with the "Swedish" mutation of APP-have the potential to affect events dependent on the normal function(s) of sAPPα. Furthermore, the increases in APP expression that occur as a result of injury or trisomy 21 may elevate the total levels of all sAPP species. To understand the implications of these events, it is critical to elucidate the biological activities of sAPPα and related moieties.
The Amyloid Cascade Hypothesis
The amyloid cascade hypothesis invokes a central role for the deposition of β−amyloid (Aβ) in the pathogenesis of AD. The amyloid precursor protein (APP) is the transmembrane glycoprotein precursor of Aβ mapping to chromosome 21. APP exists in more than 10 different forms generated by alternative mRNA splicing. Aβ is mainly a 40-42 amino acid peptide that forms one of the major constituents of neuritic plaques and vascular deposits of amyloid in AD. It is postulated that the accumulation of Aβ is the primary abnormality in ADand that its deposition finally leads to neuronal cell death and the secondary features of the disease such as NFTs. The evidence in favor of the amyloid cascade hypothesis arises from a number of observations but is broadly derived from three strands: the association of AD with Down's syndrome, the association of mutations in the APP gene and AD, and data derived from experimental neurotoxicity of Aβ.
Alzheimer's Disease and Down's Syndrome
It has long been recognized that individuals with Down's syndrome inevitably develop the pathological hallmarks of AD by their fourth decade. Down's syndrome can result from partial or complete trisomy of chromosome 21 leading to three copies of the APP gene. Overexpression of APP mRNA has been confirmed in Down's syndrome and preamyloid deposits can occur as early as the age of 12 yr. Therefore, APP overexpression in Down's syndrome may be partially or wholly responsible for the early development of AD type pathology.
APP Mutations
There were initial unsuccessful attempts to demonstrate linkage of sporadic and familial AD to APP. However, Goate et al. Subsequently demonstrated linkage to chromosome 21 in one family. Segregation of disease in this family was then demonstrated to be a result of a Val-Ile substitution at codon 717 of APP. There have now been a total of five mutations discovered in the APP gene that lead to AD. Two mutations result from the substitution of Gly or Phe at the 717 codon. Disease in two large Swedish kindreds was demonstrated to cosegregate with a double amino acid substitution at codons 690/671.
Other APP mutations have been described that lead to hereditary cerebral hemorrhage with amyloidosis (HCHWA). The first family of this type was found to have a mutation within exon 17 resulting in a Gln-Glu change at codon 693 (HCHWA-Dutch). The affected individuals presented with recurrent cerebral hemorrhages in the fourth decade. A second family exhibiting a similar phenotype has been described with an Ala-Gly substitution at position 692, which causes AD in some cases and cerebral hemorrhages and angiopathy in others. All APP mutations are 100% penetrant and lie near or within the Aβ domain close to the sites of processing by the putative secretases. APP mutations are, however, responsible for a vanishingly small proportion (approx 2%) of FAD cases. Less than 20 APP mutant pedigrees have been identified worldwide and mutations have not been identified in a large number of FAD or sporadic cases.
APP and Amyloidogenesis
In vitro studies using synthetic Aβ peptides have demonstrated that toxicity depends on the presence of a fibrillar, predominantly β pleated, sheet conformation. This form is more easily adopted by the Aβ species that is 42 amino acid residues in length (Aβ 42). It is suggested that aβ 42 production is accelerated in AD and is first deposited in preamyloid (diffuse) lesions. These become compacted over a period of many years and gradually acquire the properties of amyloid leading to neuronal damage and NFTs. All the APP mutations described to date have demonstrable effects on the production of this longer species of Aβ. Cells transfected with theSwedish double mutation at codons 670/671 of APP secrete higher levels of total Aβ. However cells expressing the codon 717 mutation produce more of the putatively more toxic Aβ 42. It has been suggested that APP mutations not only alter changes in Aβ secretion but may also influence the intracellular processing and subsequent trafficking of APP. Further in vivo evidence has been generated in transgenic experiments. Mice expressing high levels of mutant human APP show the development of diffuse amyloid plaques, and although there have been no clear neurofibrillary changes demonstrated in the animal models memory deficits have been reported in mice expressing mutant APP and amyloid fragments.
Reference:
Hooper, N. M. (Ed.). (2000). Alzheimer's disease: methods and protocols (Vol. 32). Springer Science & Business Media.
