Alzheimer’s disease is a disorder leading to neurodegeneration, progressive decline in cognitive function and premature death. This disease is accompanied by the deposition of numerous senile plaques and neurofibrillary tangles in the affected brain regions. β-Amyloid peptide (Aβ), is the main constituent of these plaques. It is a 39-42 amino acid peptide derived by proteolysis of amyloid precursor protein (APP). There appears to be a correlation between amyloid load in the cortex and disease progression on a cognitive level. We have used hippocampal long-term potentiation (LTP) in the CA1, which is a cellular model of memory, to study the effects of Aβ peptides on synaptic transmission and plasticity in vivo and also in vitro.

LTP was induced by applying a series of high frequency stimuli (HFS) comprising three episodes of 10 stimuli at 200 Hz, 10 times at 30 s intervals to the Schaffer-collateral pathway. In addition to activating the NMDA-receptor system this stimulus frequency activates L-type Ca²⁺ channels that are also involved in the induction of LTP (Freir & Herron, 2003a). In our in vivo studies, Aβ peptides were applied via intracerebroventricular (I.C.V.) injection and LTP levels were compared with those obtained following injection of water vehicle. Normal LTP was recorded following injection of vehicle or Aβ [15-25]. We found that injection of the toxic fragment Aβ[25-35] either reduced (10 nmol) or abolished (100 nmol) LTP. The reverse sequence peptide Aβ [35-35] also significantly depressed LTP (Freir et al. 2001) while lower concentrations (1 or 10 nmol) of the endogenous peptide Aβ [1-40] significantly depressed LTP (Freir and Herron, 2003b)

In view of the reported increased activation of L-type Ca²⁺ channels by Aβ (Ueda et al. 1997), we investigated the effect of L-type channel blockers on Aβ-mediated depression of LTP in vivo and also in vitro. Aβ[25-35]was applied I.C.V. and L-type blockers via intraperitoneal injection (I.P.) in vivo. All agents were bath applied in experiments that utilized the hippocampal slice preparation. We found that the VDCC blockers diltiazem and verapamil caused a dose-dependent depression of LTP in both preparations. Consistent with our previous observations, Aβ [25-35] depressed LTP, but prior treatment in either preparation with verapamil resulted in a significant reversal of the depression of LTP observed in the presence of either agent alone (Freir et al. 2003). These results indicate that verapamil, which is a phenylalkylamine, may therefore be useful in the treatment of cognitive deficits associated with Alzheimer’s disease.

Another series of experiments were performed to investigate a possible link between the depression of LTP produced by Aβ [1-40] and the α-7 nicotinic acetylcholine receptor (α-7 nAchR). The α-7-nAchR has been shown to bind Aβ-peptide with high affinity, the binding domain comprising amino acids 12-28 (Wang et al. 2000). We therefore investigated the effects of Aβ[12-28], in addition to an antagonist of the α-7 nAchR, methyllycaconitine (MLA) and nicotine on LTP. Aβ[12-28] had no effect on LTP, while MLA significantly depressed LTP. This suggests that activation of the α-7 nAchR is a requirement for LTP. Application of nicotine (I.P.) prior to I.C.V. injection of Aβ[1-40], however, caused a further significant depression of LTP compared to treatment with Aβ[1-40] alone. Nicotine therefore appears to enhance the deficit in LTP produced by Aβ[1-40], indicating that nicotine may augment the depressive effects of Aβ on synaptic plasticity in Alzheimer’ s disease.

Data will also be presented on our most recent study in which we have examined the effects of inhibitors of c-Jun-N-terminal kinase (JNK) on the depression of LTP mediated by Aβ[25-35](Costello & Herron, 2003), Aβ[1-40] and also on signalling down stream from JNK (Schmid et al. 2003).

This work was supported by the Health Research Board (Ireland), Enterprise Ireland and the Roche Foundation.