Alzheimer's disease is characterized by a widespread functional disturbance of the human brain. Fibrillar amyloid proteins are deposited inside neurons as neurofibrillary tangles and extracellularly as amyloid plaque cores and in blood vessels. The major protein subunit (A4) of the amyloid fibril of tangles, plaques and blood vessel deposits is an insoluble, highly aggregating small polypeptide of relative molecular mass 4,500. The same polypeptide is also deposited in the brains of aged individuals with trisomy 21 (Down's syndrome). We have argued previously that the A4 protein is of neuronal origin and is the cleavage product of a larger precursor protein. To identify this precursor, we have now isolated and sequenced an apparently full-length complementary DNA clone coding for the A4 polypeptide. The predicted precursor consists of 695 residues and contains features characteristic of glycosylated cell-surface receptors. This sequence, together with the localization of its gene on chromosome 21, suggests that the cerebral amyloid deposited in Alzheimer's disease and aged Down's syndrome is caused by aberrant catabolism of a cell-surface receptor.

The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor

Prions cause transmissible and genetic neurodegenerative diseases, including scrapie and bovine spongiform encephalopathy of animals and Creutzfeldt-Jakob and Gerstmann-Straussler-Scheinker diseases of humans. Infectious prion particles are composed largely, if not entirely, of an abnormal isoform of the prion protein, which is encoded by a chromosomal gene. A posttranslational process, as yet unidentified, converts the cellular prion protein into an abnormal isoform. Scrapie incubation times, neuropathology, and prion synthesis in transgenic mice are controlled by the prion protein gene. Point mutations in the prion protein genes of animals and humans are genetically linked to development of neuro-degeneration. Transgenic mice expressing mutant prion proteins spontaneously develop neurologic dysfunction and spongiform neuropathology. Understanding prion diseases may advance investigations of other neurodegenerative disorders and of the processes by which neurons differentiate, function for decades, and then grow senescent.

https://science.sciencemag.org/content/sci/252/5012/1515.full.pdf

Molecular biology of prion diseases

Alpha-1-acid glycoprotein.

Unexplained debilitating dementia or encephalopathy occurs frequently in adults and children with the acquired immune deficiency syndrome (AIDS). Brains from 15 individuals with AIDS and encephalopathy were examined by Southern analysis and in situ hybridization for the presence of human T-cell leukemia (lymphotropic) virus type III (HTLV-III), the virus believed to be the causative agent of AIDS. HTLV-III DNA was detected in the brains of five patients, and viral-specific RNA was detected in four of these. In view of these findings and the recent demonstration of morphologic and genetic relatedness between HTLV-III and visna virus, a lentivirus that causes a chronic degenerative neurologic disease in sheep, HTLV-III should be evaluated further as a possible cause of AIDS encephalopathy.

https://science.sciencemag.org/content/sci/227/4683/177.full.pdf

HTLV-III infection in brains of children and adults with AIDS encephalopathy

Hepatic lipocytes were isolated from normal rat liver and established in culture. A virtually pure isolate was obtained by fractionating enzymatically digested liver on a discontinuous gradient of arabinogalactan. Isolated cells displayed prominent rough endoplasmic reticulum and typical cytoplasmic droplets containing vitamin A. Lipocytes in primary culture were shown by immunofluorescence to secrete collagen types I, III, and IV and also laminin. Immunoassay of culture media showed that lipocytes during the first week in culture secrete type I (72.1-86.2% of total measured soluble collagen), type III (2.6-7.2%), and type IV (11.2-29.7%) collagens. Five percent of total secreted protein was collagen compared with 0.2% in similarly cultured hepatocytes and 1.7% in sinusoidal endothelial cells, as measured by the production of peptide-bound [3H]hydroxyproline in cells incubated with [3H]proline. The calculated amount of collagen synthesized by lipocytes per microgram of cellular DNA was 10-fold greater than that produced by hepatocytes and over 20-fold greater than that produced by endothelial cells. The findings indicate that collagen synthesis and secretion are specialized functions of hepatic lipocytes, and that, in cells from normal liver, this represents production primarily of type I collagen. The phenotypic resemblance of these cells to fibroblasts supports the hypothesis that lipocytes are a major source of collagen in pathologic fibrosis and may be precursors of the fibroblast-like cells observed in liver injury.

https://www.pnas.org/content/pnas/82/24/8681.full.pdf

Hepatic lipocytes: the principal collagen-producing cells of normal rat liver

The medical records, premortem biopsy specimens, and autopsy materials from 36 patients with acquired immune deficiency syndrome (AIDS) were reviewed. The majority of the patients were homosexual men. Widely metastatic Kaposi's sarcoma was seen in eight patients, while tumor was confined to the skin in an additional ten. Four patients had high-grade lymphomas. Thirty-five of the 36 patients had at least one opportunistic infection at some point in the course of their illness. Many patients had multiple infectious agents. The most consistent and striking autopsy finding was a severe depletion of lymphoid tissues. Death in the majority (83%) of the patients was attributable to opportunistic infections affecting most commonly the respiratory tract (64%) and meninges (11%). Three patients (9%) died with widely metastatic Kaposi's sarcoma and secondary hemorrhage. ( JAMA 1984;252:1152-1159)

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=jama&articleId=394154&pdfFileName=jama_252_9_018.pdf

Autopsy findings in the acquired immune deficiency syndrome.

A human complementary DNA whose protein product is considered to be the major component of scrapie-associated fibrils in Creutzfeldt-Jakob disease, kuru, and Gerstmann-Straussler syndrome has been identified and characterized. The extensive homology of this gene sequence to the hamster PrP 27- to 30-kilodalton prion protein complementary DNA clone, and its existence as a single copy in the human genome, leads to the conclusion that this is the human prion gene. This human prion gene has been mapped to human chromosome 20, negating a direct link between the prion protein and Down's syndrome or the amyloid of Alzheimer's disease.

http://science.sciencemag.org/content/sci/233/4761/364.full.pdf

Human prion protein cDNA: molecular cloning, chromosomal mapping, and biological implications

Cloned DNA probes were used to test for hepatitis B virus (HBV) DNA in the liver and serum of 14 asymptomatic hepatitis B surface antigen (HBsAg) carriers and two former carriers. The results were compared with serological markers of HBV infection and liver histopathology. Three groups of carriers were distinguished. In group I, HBV DNA was present in both liver and serum. Hepatitis B e antigen (HBeAg), a marker of viral replication, was uniformly positive in serum. In one individual in this group, viral DNA was also integrated into liver genomic DNA. In group II, lower levels of nonintegrated HBV DNA were detected in the liver, but no HBV DNA was found in the serum. HBeAg was negative and with one exception there were antibodies to HBeAg. Integrated viral DNA was present in each case. In group III, there was no detectable nonintegrated viral DNA in serum or liver, but one individual had integrated sequences. All carriers lacked antibodies to HBsAg and had antibodies to hepatitis B core antigen and demonstrated nonspecific histological abnormalities in the liver. These findings indicate significant quantitative and qualitative differences among asymptomatic HBsAg carriers and suggest that their infectivity may be highly variable.

https://www.pnas.org/content/pnas/79/23/7522.full.pdf

Hepatitis B viral DNA in liver and serum of asymptomatic carriers.

Progressive hypersomnia, memory disturbance, and vertical ophthalmoplegia developed in a 63-year-old woman. The diagnosis of Whipple's disease of the central nervous system was suggested by her presentation and results of studies using magnetic resonance imaging. Despite a one-month course of antibiotics, active Whipple's disease, localized to the central nervous system, was found at autopsy.

Edward A. Smuckler

Papers

Autopsy findings in the acquired immune deficiency syndrome.

Human prion protein cDNA: molecular cloning, chromosomal mapping, and biological implications

Hepatitis B viral DNA in liver and serum of asymptomatic carriers.

Whipple's disease confined to the central nervous system.

Pertinence of nuclear envelope nucleoside triphosphatase activity to ribonucleic acid transport.