Positional effects of presenilin-1 mutations on tau phosphorylation in cortical plaques.

Abstract

Mutations in presenilin-1 (PS-1) account for the majority of familial Alzheimer's disease (AD). While increasing Abeta42 is one mechanism whereby PS-1 mutations are thought to exert their pathogenic effect, little is known about the role of tau in PS-1 AD. This study compares staining (AT8 and tau-2), morphology and quantity of tau-immunoreactive cortical plaques in six PS-1 and five sporadic AD cases. The densities of tau-positive plaques differentiated PS-1 from sporadic AD cases. All PS-1 cases demonstrated a greater than 6-fold increase in tau-2-positive plaques. In PS-1 cases with mutations in exons 5 and 6, there was an increase in classical AD plaques containing hyperphosphorylated tau (AT8- and tau 2-positive). However, cases with exon 8 and 9 mutations had numerous cotton wool plaques containing nonhyperphosphorylated tau (tau-2-positive, AT8-negative). These findings suggest that PS-1 mutations increase tau deposition while mutation-specific cellular responses determine phosphorylation events and may influence cell death mechanisms.

• Authors: Claire E Shepherd, Gillian C Gregory, James C Vickers, William S Brooks, John B J Kwok, Peter R Schofield, Jillian J Kril, Glenda M Halliday
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 15 Issue 1 Pg. 115-9 (Feb 2004) ISSN: 0969-9961 [Print] United States
• PMID: 14751776 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Antibodies
• Membrane Proteins
• PSEN1 protein, human
• Peptide Fragments
• Presenilin-1
• amyloid beta-protein (1-42)
• tau Proteins

Topics

• Adult
• Aged
• Aged, 80 and over
• Alzheimer Disease (genetics, metabolism, pathology)
• Amyloid beta-Peptides (metabolism)
• Antibodies (immunology)
• Cerebral Cortex (metabolism, pathology, physiopathology)
• DNA Mutational Analysis
• Exons (genetics)
• Genetic Testing
• Humans
• Immunohistochemistry
• Membrane Proteins (genetics)
• Middle Aged
• Mutation (genetics)
• Neurons (metabolism, pathology)
• Peptide Fragments (metabolism)
• Phosphorylation
• Plaque, Amyloid (genetics, metabolism, pathology)
• Presenilin-1
• Up-Regulation (genetics)
• tau Proteins (metabolism)