Ralph N. Martins

Human Brain βA4 Amyloid Protein Precursor of Alzheimer's Disease: Purification and Partial Characterization

Abstract: The major component of the amyloid deposition that characterizes Alzheimers disease is the 4‐kDa βA4 protein, which is derived from a much larger amyloid protein precursor (APP). A procedure for the complete purification of APP from human brain is described. The same amino terminal sequence of APP was found in two patients with Alzheimers disease and one control subject. Two major forms of APP were identified in human brain with apparent molecular masses of 100–110 kDa and 120–130 kDa. Soluble and membrane fractions of brain contained nearly equal amounts of APP in both humans and rats. Immunoprecipitation with carboxyl terminus‐directed antibodies indicates that the soluble forms of APP are truncated. Carboxyl terminus truncation of membrane‐associated forms of human brain APP was also found to occur during postmortem autolysis. The availability of purified human brain APP will facilitate the investigation of its normal function and the events that lead to its abnormal cleavage in patients with Alzheimers disease.

Neuroinflammatory Environments Promote Amyloid-ß Deposition and Posttranslational Modification

Indisputable evidence indicates that an inflammatory response is associated with neuron and neurite damage and the deposition of amyloid s (As) and neurofibrillary tangles (NFT) in Alzheimer disease (AD) (see, ref. 1 for a comprehensive review). Just as in the periphery, where degenerating tissue and insoluble materials (resulting from trauma, embolism, and rupture) promote inflammation, these classical stimulants also promote inflammation in the AD brain. From a spatio-temporal perspective, the stimuli promoting neuroinflammation are microlocalized and are present from early preclinical to the terminal stages of AD. Likewise, the upregulation of acute-phase proteins, complement, cytokines, and other inflammatory mediators also is microlocalized and chronic.

Erratum: Clearance mechanisms of Alzheimer's amyloid-? peptide: Implications for therapeutic design and diagnostic tests (Molecular Psychiatry (2009) 14 (469-486) DOI: 10.1038/mp.2008.96)

Abbreviations: Ab, amyloid-b; AD, Alzheimer’s disease; ELISA, enzyme-linked immunosorbent assay; WB, western blot. The sample size from each paper is given in parentheses in the sample column, and the antibody used is given in parentheses in the methods column, values presented as mean±s.e.m. (except for where noted). a Values reported as mg/g total protein rather than mg/g wet tissue. b Combined Ab40 and Ab42 values for the soluble and insoluble pool. c Soluble designated as Ab40, insoluble as Ab42. d Values converted to mg/g total protein using the molecular weight of Ab40 and presented as the range. Corrigenda