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. 2001 Feb 15;21(4):1327-33.
doi: 10.1523/JNEUROSCI.21-04-01327.2001.

Use-dependent effects of amyloidogenic fragments of (beta)-amyloid precursor protein on synaptic plasticity in rat hippocampus in vivo

J H Kim  1 , R Anwyl, Y H Suh, M B Djamgoz, M J Rowan
Affiliations

Use-dependent effects of amyloidogenic fragments of (beta)-amyloid precursor protein on synaptic plasticity in rat hippocampus in vivo

J H Kim et al. J Neurosci. .

Abstract

The Alzheimer's disease-related beta-amyloid precursor protein (beta-APP) is metabolized to a number of potentially amyloidogenic peptides that are believed to be pathogenic. Application of relatively low concentrations of the soluble forms of these peptides has previously been shown to block high-frequency stimulation-induced long-term potentiation (LTP) of glutamatergic transmission in the hippocampus. The present experiments examined how these peptides affect low-frequency stimulation-induced long-term depression (LTD) and the reversal of LTP (depotentiation). We discovered that beta-amyloid peptide (Abeta1-42) and the Abeta-containing C -terminus of beta-APP (CT) facilitate the induction of LTD in the CA1 area of the intact rat hippocampus. The LTD was frequency- and NMDA receptor-dependent. Thus, although low-frequency stimulation alone was ineffective, after intracerebroventricular injection of Abeta1-42, it induced an LTD that was blocked by d-(-)-2-amino-5-phosphonopentanoic acid. Furthermore, an NMDA receptor-dependent depotentiation was induced in a time-dependent manner, being evoked by injection of CT 10 min, but not 1 hr, after LTP induction. These use- and time-dependent effects of the amyloidogenic peptides on synaptic plasticity promote long-lasting reductions in synaptic strength and oppose activity-dependent strengthening of transmission in the hippocampus. This will result in a profound disruption of information processing dependent on hippocampal synaptic plasticity.

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Figures

Fig. 1.
Fig. 1.
Amyloidogenic fragments of β-APP facilitate the induction of LTD in the rat hippocampus in vivo.A, B, Conditioning stimulation at either 3 or 10 Hz had no significant persistent effect on field EPSP slope in the CA1 area of vehicle-injected control animals. C, D, Injection of Aβ1–42 (1 pmol in 5 μl, i.c.v.) 10 min before the conditioning stimulation enabled the induction of LTD in a frequency-dependent manner, LTD being induced at 3 Hz (C) but not 10 Hz (D). E, Pretreatment with the NMDA receptor antagonist D-AP5 (100 nmol) 5 min before the Aβ1–42 prevented the induction of LTD. F, Injection of the C-terminal fragment of β-APP (CT, 2 pmol) 10 min before 10 Hz conditioning stimulation enabled the induction of LTD.Insets show typical recordings at the beginning and end of the experiments. Values are the mean ± SEM EPSP slope;n = 5–10 per group. The time of the intracerebroventricular injection is indicated by a black arrowhead, and 3 or 10 Hz stimulation is indicated by ablack bar.
Fig. 2.
Fig. 2.
The C-terminal fragment of β-amyloid precursor protein (CT) promotes the reversal of LTP. A, B, Stable LTP was induced with high-frequency stimulation (HFS, white arrow) in animals administered the vehicle either 10 min before (A) or 10 min after (B) the HFS. C, D, LTP was blocked when 1 pmol (5 μl, i.c.v.) was injected either 10 min before (C) or after (D) the HFS. Insets show typical recordings at the beginning and end of the experiments. Values are the mean ± SEM EPSP slope;n = 6–7 per group. The time of intracerebroventricular injection is indicated by a black arrowhead.
Fig. 3.
Fig. 3.
CT-facilitated reversal of LTP is NMDA receptor-dependent. Stable LTP was induced with HFS (white arrow) in animals injected with the NMDA receptor antagonist D-AP5 (100 nmol; black arrowhead) 5 min before the administration of CT 105 (1 pmol) and 5 min after the HFS (n = 7).
Fig. 4.
Fig. 4.
Time window for the block of LTP by CT.A, When CT (1 pmol) was injected 1 hr before the application of HFS (white arrow), LTP was blocked.B, CT had no effect on baseline synaptic transmission over this time period in a nontetanized pathway. C, In contrast, LTP was not affected when CT was injected 1 hr after the HFS.D, This HFS protocol induced stable LTP that lasted at least 3 hr in noninjected animals. Insets show typical recordings at the beginning and end of the experiments. Values are the mean ± SEM EPSP slope; n = 6 per group. The time of intracerebroventricular injection is indicated by black arrowheads.
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References

    1. Arriagada PV, Growdon JH, Hedleywhyte ET, Hyman BT. Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease. Neurology. 1992;42:631–639. - PubMed
    1. Baekelandt V, Moechars D, Laenen I, Lorent K, Van Leuven F. Disturbance of the glutamatergic system in mice transgenic for the amyloid precursor protein. Alzheimers Rep. 1999;2:359–368.
    1. Bear M, Abraham W. Long-term depression in the hippocampus. Annu Rev Neurosci. 1996;19:437–462. - PubMed
    1. Chapman PF, White GL, Jones MW, Cooper-Blacketer D, Marshall VJ, Irizarry M, Younkin L, Good MA, Bliss TV, Hyman BT, Younkin SG, Hsiao KK. Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice. Nat Neurosci. 1999;2:271–276. - PubMed
    1. Chen QS, Kagan BL, Hirakura Y, Xie CW. Impairment of hippocampal long-term potentiation by Alzheimer amyloid beta-peptides. J Neurosci Res. 2000;60:65–72. - PubMed

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