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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online June 18, 2001 as doi:10.1096/fj.00-0859fje. |
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Department of Pharmacology, College of Medicine, National Creative Research Initiative Centre for Alzheimer’s Dementia and Neuroscience Research Institute, MRC, Seoul National University, Seoul 110–799, South Korea;
* School of Biological Sciences, Seoul National University, Seoul 151–741, South Korea; and
Department of Anatomy, College of Medicine, Chung-Ang University, Seoul 156–756, South Korea
3Correspondence: Department of pharmacology, College of Medicine, National Creative Research Initiative Centre for Alzheimer’s Dementia, Seoul National University, Seoul, 110–799, South Korea. E-mail: yhsuh{at}plaza.snu.ac.kr
SPECIFIC AIMS
To elucidate the in vivo neurotoxicities of carboxyl-terminal fragments of amyloid precursor protein (CTs) and amyloid ß peptide (Aß), we examined cognitive changes using a Y maze and a water maze task after a single intracerebroventricular (i.c.v.) injection of the carboxyl-terminal fragment of amyloid precursor protein (APP) with 105 amino acid (CT105) (68.5, 342 and 685 pmol) or Aß1–42 (685 pmol) to mice. The changes in acetylcholine (ACh) levels and mitochondrial pyruvate dehydrogenase (PDH) activities were quantified.
PRINCIPAL FINDINGS
1. A spontaneous alteration behavior was significantly impaired by
CT105 and mildly by Aß1–42
Spatial working memory was assessed on day 14 after a single
i.c.v. injection of CT105 or Aß1–42 by
recording spontaneous alteration behavior in a Y maze. An i.c.v.
injection of CT105 (342 and 685 pmol) induced a more significant
decrease in spontaneous alteration behavior than
Aß1–42. None of the peptide treatments
affected locomotion, since no difference was observed in the total
number of arms entered during the 8 min session in the Y maze.
2. Cued, spatial, and working memory were more potently impaired by
CT105 than Aß1–42
To examine the effect of CT105 or Aß1–42
on learning and memory performances, we performed the reference memory
test, probe test, and working memory test in a water maze. The training
trials (the reference test) were carried out on days 15–19 after an
i.c.v. injection of CT105 or Aß1–42. In this
test, the escape latencies on to hidden platform of the CT105-treated
groups were significantly longer than those of saline-treated control
and Aß1–42-treated group (Fig. 1A
). The mice received a spatial probe test immediately after
the 10th training trial on day 19 after an i.c.v. injection of CT105 or
Aß1–42. There were significant group effects
on the time spent in the target quadrant where the platform had been
located during training trials (Fig. 1B
). Although there was
a significant difference between saline-treated control and the
Aß1–42-treated group, the CT105-treated mice
searched the target quadrant for a significantly less amount of time
than the Aß1–42-treated group. A working
memory (repeated acquisition) test was conducted for 3 consecutive days
from days 20 to 22 after an i.c.v. injection of CT105 or
Aß1–42 five times per day (one session). The
performances in the CT105-treated mice were significantly impaired
compared with the saline-treated control and
Aß1–42-treated mice.
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3. The ACh contents of the cerebral cortex and hippocampus were
significantly decreased in the CT105-treated groups and moderately
decreased in the Aß1–42-treatd group
The contents of ACh, a key neurotransmitter for cognitive
function, were quantified after all behavioral tests were completed.
The ACh contents of the cerebral cortex and hippocampus in the
CT105-treated groups were significantly decreased compared with the
saline-treated control and the Aß1–42-treated
group. Moderate decreases in the
Aß1–42-treated group were also observed but
not statistically significant.
4. Mitochondrial PDH activities of the cerebral cortex and
hippocampus were more significantly reduced by CT105 than
Aß1–42
PDH activities, which convert pyruvate to acetyl-CoA in
mitochondria, were significantly reduced in the cerebral cortex
(Fig. 2A
) and hippocampus (Fig. 2B
) of the CT105-treated
group vs. the saline-treated control and the
Aß1–42-treated group. PDH activities of the
Aß1–42-treated group were also decreased
compared with those of the saline-treated control group, but the degree
of reduction was much less severe than those of CT105-treated groups.
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CONCLUSIONS AND SIGNIFICANCE
Although the Aß hypothesis (derived from APP) is widely accepted in Alzheimer’s disease (AD) research, there are several discrepancies between Aß deposition and neurodegeneration or cognitive impairment that are predominant characteristics of AD. Several studies suggest that CTs has a potential to elicit neurotoxicities that are present in vivo in AD brains. We have previously shown that CT105 induced neurotoxicities both in vivo and in vitro.
In the present study, we confirmed that learning and memory could be impaired by a single i.c.v. injection of CT105 in a Y maze and a water maze task. We studied the effect of Aß1–42 and CT105 on spatial memory in detail by dividing it into two memory categories: spatial reference and working memory. Reference memory refers to memory for information that remains constant over repeated trials and therefore is trial independent. The present study revealed that spatial reference memory could be impaired by an i.c.v. injection of CT105 in the water maze training. We also observed in the probe test a clearer deficit in the CT105-treated mice than the Aß1–42-treated mice, providing additional evidence that an i.c.v. injection of CT105 results in impairment of spatial reference memory. CT105 also caused an impairment of spatial working memory, as evidenced by an increase in the escape latency in the second trial. Working memory refers to memory in which the information to be remembered changes in repeated trials. It was confirmed by repeated acquisition test of the water maze task.
Our data show some cognitive deficits of the Aß1–42-treated group in the training trials and probe test of the water maze task. However, the degree of impairment is less significant than that of the CT105-treated groups, providing evidence that neurotoxicity of CT105 is much more potent than that of Aß1–42 in inducing memory impairment.
One of the most consistent abnormalities in AD brain is a severe synaptic loss correlated with cognitive deficits involving the dysfunction and degeneration of the basal forebrain cholinergic neurons projecting to the hippocampus and cortex. In addition, levels of ACh are decreased significantly in cortical and hippocampal regions of AD brain. In the present study, we confirmed that ACh levels of cerebral cortex and hippocampus closely related to cognitive function were significantly decreased in the CT105-treated groups compared with the saline-treated control and even the Aß1–42-treated group.
Previous reports revealed that abnormally low levels of PDH activity have been correlated with chronic neurodegenerative disorders, including AD and HD, suggesting the value of studying PDH in AD. The decrease in PDH activity would induce the disturbed glucose metabolism and impaired ACh synthesis. Our present results on PDH activity and ACh level in the brains of CT105-treated mice provide a link between CT105 and the PDH inactivation. Decrease of PDH activity by CT105 would result in dysfunction of mitochondria, contributing to neuronal death through failure of energy metabolism and leading to a reduced ACh level in cholinergic neurons owing to decreased acetyl-CoA production.
Taking the present results together, we suggest that the decrease of PDH activity induced by CT105 reduces the production of acetyl-CoA, which is a metabolic product, and leads to a reduction of the ATP supply and eventually to death. As the acetyl-CoA is required for the synthesis of ACh, the decrease of PDH activity also leads to the decrease in the synthesis of ACh. Thus, it is plausible that the CT105-induced reduction of ACh levels in the brain may result in the loss of cognitive function observed in AD.
Since CT105 contains the complete Aß sequence, there is the possibility that the CT105 toxicity could result from Aß. however, we recently confirmed the direct toxicity of CT105 in various studies. These findings indicate that a region of APP other than Aß has the potential to elicit neurodegeneration and that CTs are present in vivo.
In conclusion, learning and memory were impaired by CTs at lower
concentrations than Aß. It is thought that the damage in ACh
synthesis under the influence of reduced PDH activity might exert an
important effect on cognitive deficits.FIGURE 3
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FOOTNOTES
1 To read the full text of this article, go to
http://www.fasebj.org/cgi/doi/10.1096/fj.00-0859fje ; to cite this
article, use FASEB J. (June 18, 2001)
10.1096/fj.00-0859fje 
2 S.H.C. and C.H.P. contributed equally to this
study.
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