Positional effects of presenilin-1 mutations on tau phosphorylation in cortical plaques.
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.
Shepherd
Claire E
CE
Prince of Wales Medical Research Institute, Randwick, 2031 Sydney, Australia. C.Shepherd@unsw.edu.au
Gregory
Gillian C
GC
Vickers
James C
JC
Brooks
William S
WS
Kwok
John B J
JB
Schofield
Peter R
PR
Kril
Jillian J
JJ
Halliday
Glenda M
GM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000906:Antibodies / Q000276:immunology; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005820:Genetic Testing; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1; D015854:Up-Regulation / Q000235:genetics; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D000906:Antibodies; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D016875:tau Proteins