Amyloid proteins syndrome

The cause of AD is unknown although many hypotheses abound. The gene for one of the excessive amyloid proteins(b-type) has been associated with chromosome 21 at a point not far from a locus linked to some cases of familial Alzheimer s. Victims of Down s syndrome have an extra copy of chromosome 21 and usually fall prey to AD in their 4O s should they live to that age. However no all AD victims have a 21 mutation. Other causative theories involve accumulations of aluminum in the brain or the presence of a slow virus or an infectious protein substance called a prion. 

Pike CJ, Walencewicz AJ, Glabe CG, Cotman CW (1991) In vitro aging of beta-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res 563 311—314 Prasad AS, Miale A Jr., Farid Z, Sandstead HH, Schulert AR (1963) Zinc metabolism in patients with the syndrome of iron deficiency anemia, hepatosplenomegaly, dwaifism, and hypognadism. J Lab Qin Med 61 537-549... 

The major constituent of the extracellular plaques is amyloid -protein (Ap), which aggregates into 8 nm filaments. Ap is a peptide of 40 or 42 amino acid residues and is proteolytically derived from a transmembrane glycoprotein known as P-amyloid precursor protein (jSAPP). The enzymes that cleave APP to A/3 are known as sec-retases. SAPP is widely expressed, particularly in brain, and its gene has been localized to chromosome 21q. Two major observations have aided in understanding the role of Ap peptides in the pathology of Alzheimer s disease. The first is that patients with Down syndrome have trisomy 21... 

William Klunk and Chester Mathis vadiolabelled a fluorescent dye, related to Congo Red, labeled with fluorine-18, that is bound by P-amyloid protein in plaques found in the brain of patients with AD. After years of research, they developed a dye with 34 times the affinity for amyloid than Congo Red. Some think that P-amyloid is the cause of AD, whereas others think it is the result Patients with Down syndrome carry an extra copy of the amyloid gene, and they develop brain plaques and symptoms of AD when they reach middle age. 

Neuropathies can result from mutations that alter the structure or level of expression of PNS myelin proteins (e.g. overexpression of PMP22 in Charcot-Marie-Tooth syndrome (CMT) type 1A), the metabolism of myelin lipids (e.g. metachromatic leukodystrophy), or the capacity of PNS neurons to support their axons in patients with CMT caused by mutations of KIF1B [4] or NF-L [5, 6]. Both acquired and inherited amyloid neuropathies can result from the deposition of poorly soluble proteins, for example cryoglobulins or mutant transthyretins, in and around endoneurial bloodvessels [7-9]. 

Masters, C. L., Simms, G., Weinman, N. A., Multhaup, G., McDonald, B. L., and Beyreuther, K. (1985). Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl. Acad. Sci. USA 82, 4245—4249. 

Transthyretin amyloidosis (also called familial amyloid polyneuropathy) is an autosomal dominant syndrome characterized by peripheral neuropathy. This disease results from one of five mutations identified thus far in the gene for transthyretin. Transthyretin is also called prealbumin (although it has no structural relationship to albumin) because it migrates ahead of albumin in standard electrophoresis at pH 8.6. Transthyretin is synthesized in the liver and is a normal plasma protein with a concentration of 20-40 mg/dL. It transports thyroxine and retinol binding protein (Chapter 38). The concentration of transthyretin is significantly decreased in malnutrition and plasma levels are diagnostic of disorders of malnutrition (Chapter 17). 

The amyloid-(3 peptide (A(3) has been identified as a 4 kDa hydrophobic nonglycosylated peptide consisting of 39 3 amino acid residues. It is derived by specific endoproteolytic cleavages from a 700 amino acid residue-long membrane-associated glycoprotein, named amyloid precursor protein (APP) (Citron et al., 1996 Dickson, 1997). A(3 appears in bundles of amyloid fibrils surrounded by abnormal neurites, and is believed to be the major component of the vascular and plaque filaments in individuals with AD, elderly people, and trisomy 21 carriers (Down s Syndrome) (Head and Lott, 2004). 

Glenner, G.G., and Wong, C.W. (1984). Alzheimer s disease and Down s syndrome shar-inc of a unique cerebrovascular amyloid fibril protein. Biochem. Biophys. Res. Commun. 122, 1131-1135. 

One clue to the relationship between oxidative stress and dementia is provided by people with Down syndrome, who often get Alzheimer s disease in early middle age. Again, the disease almost seems to have moved forward to an earlier time slot. We saw in Chapter 10 that people with Down syndrome suffer from oxidative stress, as a result of an imbalance in antioxidant enzymes.9 Could a rise in oxidative stress underlie the early onset of dementia in people with Down syndrome Quite probably, according to pathologists George Perry and Mark Smith, and their team at Case Western Reserve University, Cleveland, in a study published in 2000. This team measured the oxidation of proteins and DNA in people with Down syndrome, and found that a marked rise in oxidative stress always preceded the deposition of amyloid. Oxidized proteins and DNA began to build up in their late teens and 20s, with amyloid deposition occurring by their 30s. Thus, it seems that a rise in oxidative stress does foreshadow an increased risk of Alzheimer s disease, regardless of age. 

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