Absence of carboxypeptidase E leads to adult hippocampal neuronal degeneration and memory deficits

Abstract

Molecules that govern the formation, integrity and function of the hippocampus remain an important area of investigation. Here we show that absence of the proneuropeptide processing enzyme, carboxypeptidase E (CPE) in CPE knock-out (KO) mice had a profound effect on memory, synaptic physiology and the cytoarchitecture of the hippocampus in these animals. Adult CPE-KO mice displayed deficits in memory consolidation as revealed by the water-maze, object preference and social transmission of food preference tests. These mice also showed no evoked long termpotentiation. Additionally, CPE-KO mice at 4 weeks of age and older, but not at 3 weeks of age, exhibited marked degeneration specifically of the pyramidal neurons in the hippocampal CA3 region which normally expresses high levels of CPE. Immunohistochemistry revealed that the neuronal marker, NeuN, was reduced, while the glial marker, GFAP, was increased, characteristic of gliosis in the CA3 area of CPE-KO mice. Calbindin staining indicated early termination of the mossy fibers before reaching the CA1 region in these mice. Thus, absence of CPE leads to degeneration of the CA3 neurons and perturbation of the cytoarchitecture of the hippocampus. Ex vivo studies showed that overexpression of CPE in cultured hippocampal neurons protected them against H 2 O 2 oxidativestress induced cell death. These findings taken together indicate that CPE is essential for the survival of adult hippocampal CA3 neurons to maintain normal cognitive function.

Role of pGlu-Serpinin, a Novel Chromogranin A-Derived Peptide in Inhibition of Cell Death

“…All animal work was performed with the approval of the animal care and use committee (ACUC) of NICHD. Cell death induction of the cultured cells was performed as previously described (Woronowicz et al 2008). In brief, AtT-20 cells and cerebral cortical cultures were treated with 50 μM hydrogen peroxide in the presence or absence of serpinin or pGlu-serpinin for 1 day.…”

Carboxypeptidase E (NF-α1): a new trophic factor in neuroprotection

“…Indeed, CPE KO mice display memory deficits as revealed by the Morris water maze, object preference, and social transmission of food preference [17] , and show no evoked long-term potentiation (which is required for memory and learning) in hippocampal slices. Neonatal CPE KO mice also exhibit a significant delay in eye opening, which reflects a developmental delay in the central nervous system (Cawley et al ., unpublished data).…”

“…In addition, Cpe fat/fat mutant mice lacking CPE exhibit anxiety- and/or depression-like behaviors [18] . CPE KO mice at 4 weeks of age or older, but not at 3 weeks, exhibit marked degeneration of the CA3 region which normally expresses high levels of CPE [17] . The neurodegeneration in CPE KO mice was initially thought to be a developmental defect.…”

“…Also, low-potassium-induced apoptosis is significantly increased in CPE +/ cerebellar granule neurons (CGNs) in comparison to CPE +/+ CGNs, indicating that CPE plays a neuroprotective role in this type of neuron as well as hippocampal neurons [21] . More direct evidence came from a study showing that transduction of an adenovirus carrying CPE into primary cultured hippocampal neurons, causing over-expression of CPE, protects against hydrogen peroxide-induced neurotoxicity [17] . Although the mechanism was unknown, CPE was assumed to function intracellularly to process some precursor protein that had neuroprotective activity.…”

Neuroprotective Protein and Carboxypeptidase E

“…Furthermore, calbindin staining showed early termination of the mossy fibers before reaching the CA1 region in the hippocampus of CPE −/− mice. Ex vivo studies revealed that apoptosis of primary cultured rat hippocampal neurons induced by hydrogen peroxide, a reactive oxygen species (ROS), was dramatically suppressed when CPE was overexpressed in these cells (Woronowicz et al 2008). These findings indicate that CPE is essential for survival of CA3 neurons and maintenance of hippocampal mossy fiber morphology as well as function, including consolidation of memory.…”