Selective apoptosis induction in the hippocampal mossy fiber pathway by exposure to CT105, the C-terminal fragment of Alzheimer's amyloid precursor protein.
Beta-amyloid protein (Abeta), a proteolytic byproduct of Alzheimer's amyloid precursor protein (APP), has been shown to play a central role in the development of Alzheimer's disease (AD). In addition, recent studies strongly suggest that other byproducts of proteolysis, such as C-terminal fragments of APP (APP-CTF), are also critically involved in the AD pathology. To explore this possibility, we investigated the histopathological changes induced by repeated low-dose intrahippocampal injection of a recombinant 105 amino acid C-terminal fragment of APP (CT105). First, we carried out a behavioral analysis by using the three-panel runway task, and found that the working memory was significantly impaired by CT105 exposure. Then, via propidium iodide staining, we encountered a number of cells exhibiting fragmented or shrank nuclei in the mossy fiber pathway (stratum lucidum and dentate hilus) in CT105-treated rats. These cells were positive for single-stranded DNA (ssDNA), an apoptosis-specific marker, and thus were considered to be apoptotic. Some of the ssDNA-positive cells were also positive for somatostatin. But neither ionized calcium-binding adapter molecule 1 (Iba1) nor S100beta occurred in ssDNA-positive cells. These findings suggest that CT105 induces apoptotic changes in cells of neuronal origin. Quantitative analysis showed that the densities of ssDNA-positive cells in the mossy fiber pathway were significantly higher in CT105-treated rats than in control animals. The present results suggest that CT105 causes dysfunction in the hippocampal mossy fiber system, and also provide some key to understand the relationship between APP-CTF and glutamatergic synaptic dysregulation in AD.
Jinno
Shozo
S
Department of Anatomy and Neurobiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. sjnno@med.kyushu-u.ac.jp
Araki
Kumiko
K
Matsumoto
Yuji
Y
Suh
Yoo-Hun
YH
Yamamoto
Tsuneyuki
T
D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000032:analysis; D007150:Immunohistochemistry; D008297:Male; D008570:Memory, Short-Term; D008840:Microfilament Proteins; D019599:Mossy Fibers, Hippocampal / Q000737:chemistry / Q000473:pathology / Q000502:physiology*; D009414:Nerve Growth Factors / Q000378:metabolism; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D010784:Photomicrography; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism
C100745:Aif1 protein, rat; D016564:Amyloid beta-Protein Precursor; D002135:Calcium-Binding Proteins; D004277:DNA, Single-Stranded; D008840:Microfilament Proteins; D009414:Nerve Growth Factors; D010446:Peptide Fragments; D011994:Recombinant Proteins; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins