Behavioral and Neuropathologic Changes Induced by Central Injection of Carboxyl‐Terminal Fragment of β‐Amyloid Precursor Protein in Mice

Alzheimer's disease (AD) is characterized by cognitive impairment and excessive deposition of neurite plaques (NPs). Although the pathogenic mechanism of AD is not exactly known, there is increasing evidence that amyloid beta protein (Aβ), which is the major constituent of NPs and is derived from amyloid precursor protein (APP), plays a key role in the neuronal degeneration in AD. However, because there are several discrepancies between Aβ deposition and neurodegeneration or cognitive impairment in AD, the possible effects of other cleavage products of APP need to be explored. We previously showed that a recombinant carboxylterminal 105 amino acid fragment of APP (CT105) induced neurotoxicities both in vitro and in vivo. However, it is unclear whether learning and memory impairments and neurochemical changes are induced by CT105. To elucidate the in vivo neurotoxicities of Aβ and CT105, we examined behavioral changes using a Y-maze and a water maze task following a single intracerebroventricular injection of CT105 (68.5, 342 and 685 pmol) or Aβ 1-42 (685 pmol) to mice. We also quantified the changes in the acetylcholine (ACh) level and assayed mitochondrial pyruvate dehydrogenase (PDH) activity. CT105 caused much more significant impairments in cued, spatial, and working memory performances of mice in Y-maze and water maze tasks in a dose-dependent manner than Aβ 1-42 . Also, the mice injected with CT105 revealed significant decreases in ACh levels and reduced PDH activities in the cerebral cortex and hippocampus compared with the saline-treated control and Aβ 1-42 -treated groups. These results suggest that learning and memory impairment induced by centrally administered CT105 is in some way related to the reduced ACh levels and mitochondrial PDH activities and that CT105 is more potent than Aβ in inducing cognitive dysfunction.Key words: amyloid beta peptide • learning and memory • acetylcholine • pyruvate dehydrogenase lzheimer's disease (AD) is characterized clinically by progressive loss of cognitive function accompanied by deterioration of the central cholinergic system and histologically by neurite plaques (NPs) and neurofibrillary tangles (NFTs) in the brain (1). It has also been reported that the levels of acetylcholine (ACh) were decreased significantly in the cortical and hippocampal regions of the AD brain (2). It has been suggested that a diminution of chloinergic function is associated with the severity of cognitive dysfunction and progressive memory loss in patients (3).NPs are composed of β-amyloid protein (Aβ), 39-42 amino acid long, derived from the transmembrane region of the amyloid precursor protein (APP). Widely associated with the pathogenesis of AD and Down's syndrome (DS) (4, 5), APP has a single membrane-spanning domain, a large extracellular N-terminus, and a short cytoplasmic C-terminus. Three alternative processing pathways for APP involve enzymatic cleavages: α-, β-, and γ-secretase. α-Secretase cleaves APP within the Aβ domain and generates a large secreted form of APP (sAPPα), ther...

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“…injection of CT105 (28). In this study, we confirmed that cued, spatial, and working memory also could be impaired by a single i.c.v.…”

Section: Discussionsupporting

confidence: 82%

Memory impairment and cholinergic dysfunction by centrally administered Aβ and carboxyl‐terminal fragment of Alzheimer's APP in mice

et al. 2001

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“…The acetylcholine level in the cerebral cortex and hippocampus was significantly decreased, accompanyied by reduction of mitochondrial pyruvate dehydrogenase activity (86). Also CTF induced reactive gliosis in the neocortex and hippocampus and neurodegeneration in the neocortex (85). These results indicate that centrally administered CTF induces behavioral impairment and neuropathologic changes, suggesting a direct toxic effect of CTF per se.…”

Section: Effects Of Ctf On the Calcium Homeostasis In The Neuronal Cellsmentioning

confidence: 85%

“…Learning and memory impairment and neuropathological changes in centrally injected CTF mice and Tg mice overexpressing CT100 and double Tg mice overexpressing CT100 and mutant tau CTF caused significant impairments in cued, spatial, and working memory performances in a dose-dependent manner following a single intracerebroventricular injection of CTF to mice (85,86). The acetylcholine level in the cerebral cortex and hippocampus was significantly decreased, accompanyied by reduction of mitochondrial pyruvate dehydrogenase activity (86).…”

Section: Effects Of Ctf On the Calcium Homeostasis In The Neuronal Cellsmentioning

confidence: 98%

Pathophysiological Roles of Amyloidogenic Carboxy-Terminal Fragments of the β-Amyloid Precursor Protein in Alzheimer’s Disease

Chang

Suh

2005

J Pharmacol Sci

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Abstract. Several lines of evidence suggest that some of the neurotoxicity in Alzheimer's disease (AD) is attributed to proteolytic fragments of amyloid precursor protein (APP) and bamyloid (Ab) may not be the sole active component involved in the pathogenesis of AD. The potential effects of other cleavage products of APP need to be explored. The CTFs, carboxyterminal fragments of APP, have been found in AD patients' brain and reported to exhibit much higher neurotoxicity in a variety of preparations than Ab. Furthermore CTFs are known to impair calcium homeostasis and learning and memory through blocking LTP, triggering a strong inflammatory reaction through MAPKs-and NF-kB-dependent astrocytosis and iNOS induction. Recently, it was reported that CTF translocated into the nucleus, binding with Fe65 and CP2, and in turn, affected transcription of genes including glycogen synthase kinase-3b, which results in the induction of tau-rich neurofibrillary tangles and subsequently cell death. Spatial memory of transgenic (Tg) mice overexpressing CT100 was significantly impaired and CTFs were detected in the neurons as well as in plaques of the Tg mice and double Tg mice carrying CT100 and mutant tau. In this review, we summarize observations indicating that both CTF and Ab may participate in the neuronal degeneration in the progress of AD by differential mechanisms.

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“…Overexpression of β-CTF in neurons of transgenic mice led to hippocampal degeneration as well as deficits in memory and long-term potentiation [33,34].…”

Section: Discussionmentioning

confidence: 99%

Article Withdrawal Statement

2016

International Journal of Neuroscience

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Both senile plaques (SP) and intracellular neurofibrillary tangles (NFT) are important pathological characteristics in Alzheimer's disease (AD). However, the relationship between Aβ deposition and tau hyperphosphorylation is unknown. In this study, increased levels of full-length amyloid precursor protein (APP), APP c terminal fragment (β-CTF), and BACE1 were found in Streptozotocin (STZ)-induced tau hyperphosphorylation models by quantitative polymerase chain reaction (PCR), Western blotting, and immunohistochemistry methods. In previous studies, few strategies focusing on inhibiting β secretase in tau hyperphosphorylation model were utilized. Here, BACE1 RNAi was used to treat the STZ-induced tau hyperphosphorylation animal models. BACE1 RNAi treatment improved the behavior ability of animal models and reduced the amount of Aβ1-40 and Aβ1-42 accompanied by a decrease in the levels of BACE1 and β-CTF. Our results demonstrated that neurological defect and neurotoxic fragments including Aβ and β-CTF were eliminated by BACE1 RNAi in tau hyperphosphorylated model, implying efficiency and safety of BACE1RNAi treatment against AD.

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Behavioral and Neuropathologic Changes Induced by Central Injection of Carboxyl‐Terminal Fragment of β‐Amyloid Precursor Protein in Mice

Cited by 57 publications

References 14 publications

Memory impairment and cholinergic dysfunction by centrally administered Aβ and carboxyl‐terminal fragment of Alzheimer's APP in mice

Memory impairment and cholinergic dysfunction by centrally administered Aβ and carboxyl‐terminal fragment of Alzheimer's APP in mice

Pathophysiological Roles of Amyloidogenic Carboxy-Terminal Fragments of the β-Amyloid Precursor Protein in Alzheimer’s Disease

Article Withdrawal Statement

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