In patients with Alzheimer's disease, amyloid fibrils that are aggregates of A4 protein subunits are deposited in the brain. A similar process occurs at an earlier age in persons with Down...

https://www.nejm.org/doi/pdf/10.1056/NEJM198906013202203?listPDF=true

Amyloid A4 protein and its precursor in Down's syndrome and Alzheimer's disease.

The cloned cDNA encoding the rat cognate of the human A4 amyloid precursor protein was isolated from a rat brain library. The predicted primary structure of the 695-amino acid-long protein displays 97% identity to its human homologue shown previously to resemble an integral membrane protein. The protein was detected in rodent brain and muscle by Western blot analysis. Using in situ hybridization and immunocytochemistry on rat brain sections, we discovered that rat amyloidogenic glycoprotein (rAG) and its mRNA are ubiquitously and abundantly expressed in neurons indicating a neuronal original for the amyloid deposits observed in humans with Alzheimer's disease (AD). The protein appears in patches on or near the plasma membranes of neurons suggesting a role for this protein in cell contact. Highest expression was seen in rat brain regions where amyloid is deposited in AD but also in areas which do not contain deposits in AD. Since amyloid deposits are rarely observed in rat brain, we conclude that high expression of AG is not the sole cause of amyloidosis.

Alzheimer's disease amyloidogenic glycoprotein: expression pattern in rat brain suggests a role in cell contact.

We have isolated a cDNA from a mouse brain library that encodes a protein whose predicted amino acid sequence is 42% identical and 64% similar to that of the amyloid beta protein precursor (APP). This 653-amino acid protein, which we have termed the amyloid precursor-like protein (APLP), appears to be similar to APP in overall structure as well as amino acid sequence. The amino acid homologies are concentrated within three distinct regions of the two proteins where the identities are 47%, 54%, and 56%. The APLP cDNA hybridizes to two messages of approximately 2.4 and 1.6 kilobases that are present in mouse brain and neuroblastoma cells. Polyclonal antibodies raised against a peptide derived from the C terminus of APLP stain the cytoplasm in a pattern reminiscent of Golgi staining. In addition to APP, APLP also displays significant homology to the Drosophila APP-like protein APPL and a rat testes APP-like protein. These data indicate that the APP gene is a member of a strongly conserved gene family. Studies aimed at determining the functions of the proteins encoded by this gene family should provide valuable clues to their potential role in Alzheimer disease neuropathology.

https://www.pnas.org/content/pnas/89/22/10758.full.pdf

Identification of a mouse brain cDNA that encodes a protein related to the Alzheimer disease-associated amyloid beta protein precursor.

This study gathers together all of the important nonradioactive labelling techniques for nucleic acids, proteins, glycoproteins and glycolipids like DIG, Biotin, BrdU, Sulfone, Immunogold, Silver Enhancement and SNAP, as well as the standard procedures for optical, chemical, biological, electrochemiluminescent and fluorescent detection. Additionally, applications for the use of non-isotopically labelled biomolecules are described. Specific protocols are given for hybridization analysis such as blot, colony/plaque and in-situ hybridization formats, and also non-radioactive techniques for nucleic acid sequencing and amplification. Each chapter contains a short introduction, a detailed description of the method with lab protocols, trouble-shooting tips and references.

Nonradioactive labeling and detection of biomolecules

Senile plaques (SP) are one of the characteristic pathological lesions of Alzheimer's disease (AD). They are also seen in the brains of some non-demented individuals as an age-related change. Identification of clinical conditions associated with these “incidental” SP could provide insight into AD pathogenesis. We have examined the presence of SP in lobectomy specimens (n=101) removed in the surgical treatment of temporal lobe epilepsy (TLE). SP were present in 10 specimens from epileptic patients aged 36 to 61 years and the presence of SP correlated positively with patient age. No other significant AD-related pathology was identified and no patients showed any evidence of dementia on neuropsychological testing. When compared with temporal lobe tissue from non-demented, non-epileptic autopsy controls (n=406), the density and distribution of SP was the same. The age-related incidence of SP however, was significantly greater in the epileptics. This suggests that some aspects of TLE has a positive influence on the formation of SP.

Senile plaques in temporal lobe epilepsy

Cloning and sequence analysis revealed the putative amyloid A4 precursor (pre-A4) of Alzheimer's disease to have characteristics of a membrane-spanning glycoprotein In addition to brain, pre-A4 mRNA was found in adult human muscle and other tissues We demonstrate by in situ hybridization that pre-A4 mRNA is present in adult human muscle, in cultured human myoblasts and myotubes Immunofluorescence with antipeptide antibodies shows the putative pre-A4 protein to be expressed in adult human muscle and associated with some but not all nuclear envelopes Despite high levels of a single 35-kb pre-A4 mRNA species in cultured myoblasts and myotubes, the presence of putative pre-A4 protein could not be detected by immunofluorescence This suggests that putative pre-A4 protein is stabilized and therefore functioning in the innervated muscle tissue but not in developing, ie non-innervated cultured muscle cells The selective localization of the protein on distinct nuclear envelopes could reflect an interaction with motor endplates

https://www.embopress.org/doi/pdf/10.1002/j.1460-2075.1988.tb02822.x

Localization of the putative precursor of Alzheimer's disease-specific amyloid at nuclear envelopes of adult human muscle.

The major protein subunit of the amyloid fibril in Alzheimer’s disease is a small molecule of 42 residues (termed A4). It is derived from a larger precursor (PreA4), the gene for which is located on chromosome 21, in close proximity to the region involved in Down’s syndrome. The predicted structure of PreA4 suggests that it is an integral membrane glycoprotein. Knowledge of the mechanisms by which PreA4 is degraded to A4 may contribute to a better understanding of the cause of Alzheimer’s disease. Similarly, the amyloid fibril in the unconventional virus diseases is composed of the PrP molecule, which in turn is derived from a neuronal membrane glycoprotein. An understanding of the process by which the PrP molecule is converted into an amyloidogenic molecule may shed some light on the nature of the infectious unit.

The Molecular Basis of Cerebral Amyloidosis in Alzheimer’s Disease and the Unconventional Virus Diseases

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Localization of the putative precursor of Alzheimer's disease-specific amyloid at nuclear envelopes of adult human muscle.

The Molecular Basis of Cerebral Amyloidosis in Alzheimer’s Disease and the Unconventional Virus Diseases