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Patrick N. Pompl, MS; Shrishailam Yemul, PhD; Zhongmin Xiang, PhD; Lap Ho, PhD; Varham Haroutunian, PhD; Dushyant Purohit, MD; Richard Mohs, MD; Giulio Maria Pasinetti, MD, PhD

Arch Neurol. 2003;60:369-376.

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.

From the Neuroinflammation Research Laboratories, Department of Psychiatry (Mr Pompl and Drs Yemul, Xiang, Ho, and Pasinetti), and the Departments of Pathology (Dr Purohit) and Psychiatry (Dr Mohs), Mount Sinai School of Medicine, New York, NY; and the Department of Psychiatry, Bronx Veteran Affairs Medical Center, Bronx, NY (Dr Haroutunian).

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