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PGC-1alpha expression decreases in the Alzheimer disease brain as a function of dementia.
Arch Neurol. 2009 Mar; 66(3):352-61.AN

Abstract

OBJECTIVES

To explore mechanisms through which altered peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) expression may influence Alzheimer disease (AD) amyloid neuropathology and to test the hypothesis that promotion of PGC-1alpha expression in neurons might be developed as a novel therapeutic strategy in AD.

DESIGN

Case-control. Patients Human postmortem brain (hippocampal formation) samples from AD cases and age-matched non-AD cases.

RESULTS

Using genome-wide complementary DNA microarray analysis, we found that PGC-1alpha messenger RNA expression was significantly decreased as a function of progression of clinical dementia in the AD brain. Following confirmatory real-time polymerase chain reaction assay, we continued to explore the role of PGC-1alpha in clinical dementia and found that PGC-1alpha protein content was negatively associated with both AD-type neuritic plaque pathology and beta-amyloid (Abeta)(X-42) contents. Moreover, we found that the predicted elevation of amyloidogenic Abeta(1-42) and Abeta(1-40) peptide accumulation in embryonic cortico-hippocampal neurons derived from Tg2576 AD mice under hyperglycemic conditions (glucose level, 182-273 mg/dL) coincided with a dose-dependent attenuation in PGC-1alpha expression. Most importantly, we found that the reconstitution of exogenous PGC-1alpha expression in Tg2576 neurons attenuated the hyperglycemic-mediated beta-amyloidogenesis through mechanisms involving the promotion of the "nonamyloidogenic" alpha-secretase processing of amyloid precursor protein through the attenuation of the forkheadlike transcription factor 1 (FoxO3a) expression.

CONCLUSION

Therapeutic preservation of neuronal PGC-1alpha expression promotes the nonamyloidogenic processing of amyloid precursor protein precluding the generation of amyloidogenic Abeta peptides.

Authors+Show Affiliations

Department of Psychiatry, Mount Sinai School of Medicine, Bronx, NY, USA. weiping.qin@mssm.edu.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

19273754

Citation

Qin, Weiping, et al. "PGC-1alpha Expression Decreases in the Alzheimer Disease Brain as a Function of Dementia." Archives of Neurology, vol. 66, no. 3, 2009, pp. 352-61.
Qin W, Haroutunian V, Katsel P, et al. PGC-1alpha expression decreases in the Alzheimer disease brain as a function of dementia. Arch Neurol. 2009;66(3):352-61.
Qin, W., Haroutunian, V., Katsel, P., Cardozo, C. P., Ho, L., Buxbaum, J. D., & Pasinetti, G. M. (2009). PGC-1alpha expression decreases in the Alzheimer disease brain as a function of dementia. Archives of Neurology, 66(3), 352-61. https://doi.org/10.1001/archneurol.2008.588
Qin W, et al. PGC-1alpha Expression Decreases in the Alzheimer Disease Brain as a Function of Dementia. Arch Neurol. 2009;66(3):352-61. PubMed PMID: 19273754.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PGC-1alpha expression decreases in the Alzheimer disease brain as a function of dementia. AU - Qin,Weiping, AU - Haroutunian,Vahram, AU - Katsel,Pavel, AU - Cardozo,Christopher P, AU - Ho,Lap, AU - Buxbaum,Joseph D, AU - Pasinetti,Giulio M, PY - 2009/3/11/entrez PY - 2009/3/11/pubmed PY - 2009/4/16/medline SP - 352 EP - 61 JF - Archives of neurology JO - Arch. Neurol. VL - 66 IS - 3 N2 - OBJECTIVES: To explore mechanisms through which altered peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) expression may influence Alzheimer disease (AD) amyloid neuropathology and to test the hypothesis that promotion of PGC-1alpha expression in neurons might be developed as a novel therapeutic strategy in AD. DESIGN: Case-control. Patients Human postmortem brain (hippocampal formation) samples from AD cases and age-matched non-AD cases. RESULTS: Using genome-wide complementary DNA microarray analysis, we found that PGC-1alpha messenger RNA expression was significantly decreased as a function of progression of clinical dementia in the AD brain. Following confirmatory real-time polymerase chain reaction assay, we continued to explore the role of PGC-1alpha in clinical dementia and found that PGC-1alpha protein content was negatively associated with both AD-type neuritic plaque pathology and beta-amyloid (Abeta)(X-42) contents. Moreover, we found that the predicted elevation of amyloidogenic Abeta(1-42) and Abeta(1-40) peptide accumulation in embryonic cortico-hippocampal neurons derived from Tg2576 AD mice under hyperglycemic conditions (glucose level, 182-273 mg/dL) coincided with a dose-dependent attenuation in PGC-1alpha expression. Most importantly, we found that the reconstitution of exogenous PGC-1alpha expression in Tg2576 neurons attenuated the hyperglycemic-mediated beta-amyloidogenesis through mechanisms involving the promotion of the "nonamyloidogenic" alpha-secretase processing of amyloid precursor protein through the attenuation of the forkheadlike transcription factor 1 (FoxO3a) expression. CONCLUSION: Therapeutic preservation of neuronal PGC-1alpha expression promotes the nonamyloidogenic processing of amyloid precursor protein precluding the generation of amyloidogenic Abeta peptides. SN - 1538-3687 UR - https://www.unboundmedicine.com/medline/citation/19273754/PGC_1alpha_expression_decreases_in_the_Alzheimer_disease_brain_as_a_function_of_dementia_ L2 - https://jamanetwork.com/journals/jamaneurology/fullarticle/10.1001/archneurol.2008.588 DB - PRIME DP - Unbound Medicine ER -