Altered expression levels of the protein phosphatase 2A ABalphaC enzyme are associated with Alzheimer disease pathology.
The formation of amyloid-containing senile plaques and tau-rich neurofibrillary tangles are central events in Alzheimer disease (AD) pathogenesis. Significantly, ABalphaC, a major protein phosphatase 2A (PP2A) holoenzyme, specifically binds to and dephosphorylates tau. Deregulation of PP2A results in tau hyperphosphorylation in vivo. Here, we compared the expression levels and distribution of PP2A subunits in various brain regions from autopsy cases of AD and aged controls with or without histological evidence of age-related neurofibrillary degeneration. Immunoblotting analyses revealed that there was a significant reduction in the total amounts of ABalphaC in AD frontal and temporal cortices that matched the decrease in PP2A activity measured in the same brain homogenates. Immunohistochemical studies showed that neuronal ABalphaC expression levels were significantly and selectively decreased in AD-affected regions and in tangle-bearing neurons, but not in AD cerebellum and in non-AD dementias. Reduced neuronal ABalphaC immunoreactivity closely correlated with tangle load, but not plaque burden, suggesting that ABalphaC dysfunction contributes to AD tau pathology. Glial cells within senile plaques were also positive for ABalphaC. Increased glial PP2A immunoreactivity was observed in both AD and non-AD cases and may play a role in the brain's response to general inflammatory processes and amyloidogenesis.
Sontag
Estelle
E
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9073, USA. Estelle.Sontag@UTSouthwestern.edu
Luangpirom
Ampa
A
Hladik
Christa
C
Mudrak
Ingrid
I
Ogris
Egon
E
Speciale
Samuel
S
White
Charles L
CL
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology*; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D003704:Dementia / Q000201:enzymology / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000201:enzymology; D009457:Neuroglia / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000096:biosynthesis*; D058225:Plaque, Amyloid / Q000473:pathology; D054648:Protein Phosphatase 2
D007527:Isoenzymes; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2