The Journal of Neuroscience, January 11, 2006, 26(2):429-434; doi:10.1523/JNEUROSCI.3961-05.2006
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Neurobiology of Disease
Expression of a Familial Alzheimer's Disease-Linked Presenilin-1 Variant Enhances Perforant Pathway Lesion-Induced Neuronal Loss in the Entorhinal Cortex
Orly Lazarov,1
Letia D. Peterson,2
Daniel A. Peterson,2 and
Sangram S. Sisodia1
1Department of Neurobiology, Pharmacology and Physiology, The University of Chicago, Chicago, Illinois 60637, and 2Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064
Alzheimer's disease (AD) is characterized by neuronal loss in the hippocampus and entorhinal cortex that is manifested by progressive memory impairment and cognitive decline. Autosomal-dominant, familial forms of AD (FAD) are caused by mutations in genes encoding amyloid precursor protein, presenilin-1 (PS1), and presenilin 2. Although it is established that expression of mutant PS1 variants leads to increased production of highly fibrillogenic amyloid
42 (A42) peptides that deposit in the brains of patients with AD, the mechanism(s) by which A deposition and expression of mutant genes induce lamina- and region-specific vulnerability of neuronal populations is not known. We have examined the hypothesis that expression of transgene-encoded FAD-linked mutant PS1 variants in entorhinal cortex neurons exacerbates the vulnerability of these cells to lesion-induced neuronal loss. To test this notion, we transected the perforant pathway (PP) of transgenic mice harboring either wild-type human PS1 (PS1HWT) or the FAD-linked mutant PS1
E9 variant and examined neuronal survival in layer II of the entorhinal cortex (ECL2). Remarkably, PP transections lead to marked reductions in the numbers of ECL2 neurons in the ECL2 of mice expressing mutant PS1, compared with ECL2 neurons in PP-lesioned PS1HWT mice. Finally, and in contrast to studies in nontransgenic mice and in mice expressing PS1HWT, ECL2 neurons that express mutant PS1 and the calcium binding protein calbindin-D28k in ECL2 are also susceptible to lesion-induced neuronal loss. We conclude that expression of FAD-linked mutant PS1 variants enhances the vulnerability of neurons in the entorhinal cortex to PP lesion-induced cytotoxicity.
Key words: Alzheimer's disease; neurodegeneration; presenilin; perforant pathway; entorhinal cortex; neuronal death
Received Sep 19, 2005;
revised November 7, 2005;
accepted November 14, 2005.
