Protein markers for Alzheimer disease in the frontal cortex and cerebellum.
OBJECTIVE
To compare proteins related to Alzheimer disease (AD) in the frontal cortex and cerebellum of subjects with early-onset AD (EOAD) with or without presenilin 1 (PS1) mutations with sporadic late-onset AD (LOAD) and nondemented control subjects.


METHODS
Immunohistochemistry, immunoblot analysis, and ELISA were used to detect and assess protein levels in brain.


RESULTS
In EOAD and to a lesser extent in LOAD, there was increased amyloid beta (Abeta) deposition (by immunohistochemistry), increased soluble Abeta (by immunoblot analysis), and specific increases in Abeta40 and Abeta42 (by ELISA) in the frontal cortex and, in some cases, in the cerebellum. Surprisingly, immunoblot analysis revealed reduced levels of PS1 in many of the subjects with EOAD with or without PS1 mutations. In those PS1 mutation-bearing subjects with the highest Abeta, PS1 was barely, if at all, detectable. This decrease in PS1 was specific and not attributable solely to neuronal loss because amyloid precursor protein (APP) and the PS1-interacting protein beta-catenin levels were unchanged.


CONCLUSIONS
This study shows that in the frontal cortex and cerebellum from Alzheimer disease patients harboring certain presenilin 1 mutations, high levels of amyloid beta are associated with low levels of presenilin 1. The study provides the premise for further investigation of mechanisms underlying the downregulation of presenilin 1, which may have considerable pathogenic and therapeutic relevance.
Verdile
G
G
The Sir James McCusker Alzheimer's Disease Research Unit, School of Psychiatry & Clinical Neurosciences, The University of Western Australia, Hollywood Private Hospital, Nedlands, WA, Australia.
Gnjec
A
A
Miklossy
J
J
Fonte
J
J
Veurink
G
G
Bates
K
K
Kakulas
B
B
Mehta
P D
PD
Milward
E A
EA
Tan
N
N
Lareu
R
R
Lim
D
D
Dharmarajan
A
A
Martins
R N
RN
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015536:Down-Regulation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1; D015854:Up-Regulation / Q000502:physiology
D016229:Amyloid beta-Peptides; D015415:Biomarkers; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)