Caspase Gene Expression in the Brain as a Function of the Clinical Progression of Alzheimer Disease

• Published in: Archives of neurology (Chicago) Vol. 60; no. 3; pp. 369 - 376
• Main Authors: Pompl, Patrick N, Yemul, Shrishailam, Xiang, Zhongmin, Ho, Lap, Haroutunian, Varham, Purohit, Dushyant, Mohs, Richard, Pasinetti, Giulio Maria
• Format: Journal Article
• Language: English
• Published: Chicago, IL American Medical Association 01.03.2003
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - enzymology; Alzheimer Disease - pathology; Apoptosis; Biological and medical sciences; Biomarkers; Brain - enzymology; Brain - pathology; Caspases - genetics; Cognition; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Progression; Female; Gene Expression Regulation, Enzymologic; Humans; In Situ Nick-End Labeling; Male; Medical sciences; Neurology; Poly(ADP-ribose) Polymerases - metabolism; RNA, Messenger - analysis; Human; Nervous system diseases; Enzyme; Alzheimer disease; Central nervous system; Caspase; Gene expression; Cerebral disorder; Peptidases; Central nervous system disease; Immunoblotting assay; Hydrolases; Evolution; Degenerative disease; Apoptosis; Brain (vertebrata)
• ISSN: 0003-9942; 2168-6149; 1538-3687; 2168-6157
• DOI: 10.1001/archneur.60.3.369

BACKGROUND Caspase gene expression has previously been reported in terminal Alzheimer disease (AD) brain, but, currently, little is known about the temporal pattern of caspase gene expression relative to the onset and clinical progression of AD. OBJECTIVE To derive a profile of caspase gene expression and proapoptotic indexes as a function of the clinical and neuropathologic progression of AD dementia. SETTING AND PATIENTS Postmortem survey of nursing home patients characterized clinically by Clinical Dementia Rating (CDR) and neuropathologically by Consortium to Establish a Registry for Alzheimer's Disease criteria. DESIGN AND OUTCOME MEASURES To assess messenger RNA expression of caspase-1, -2L, -2S, -3, -5, -6, -7, -8, and -9; apoptotic cell death by TUNEL assay; and poly (ADP-ribose) polymerase cleavage in postmortem brain tissue samples from cognitively normal (CDR 0), high risk of developing AD dementia (CDR 0.5), and severe dementia (CDR 5) cases. RESULTS Compared with CDR 0 cases, elevated messenger RNA expression of caspase-1 and caspase-7 in the entorhinal cortex of CDR 0.5 cases coincided with increased poly (ADP-ribose) polymerase cleavage but not apoptotic cell injury. In the entorhinal cortex of CDR 5 cases, we found elevation of caspase-1, -2L, -3, -5, -6, -7, -8, and -9 and a greater than 4-fold increase in TUNEL-positive cells. Caspase messenger RNA expression was closely associated with neurofibrillary tangle and, to a lesser extent, neuritic plaque density. CONCLUSIONS Proapoptotic mechanisms may be at play early in the onset of AD (before overt signs of apoptosis) and may be a conditional factor for later apoptotic cell injury or death. These data have relevance to potential therapeutic interventions for AD using selective caspase inhibitors.Arch Neurol. 2003;60:369-376-->