Impaired hippocampal and thalamic acetylcholine release in P301L tau-transgenic mice.

We evaluated acetylcholine release by microdialysis in 10 month old control and JNPL3 mice which carry a mutant tau gene (P301 L). Three brain regions were compared: hippocampus and thalamus which receive cholinergic input from the basal forebrain, and the red nucleus which receives cholinergic projections from brain stem nuclei. Cognitive and motor functions of the mice were largely normal. In microdialysis experiments, we found significant reductions in basal ACh levels in hippocampus and thalamus, but not in the red nucleus. ACh release was impaired most strongly (by 50%) when a physiological stimulus was applied, i.e. exploration of a novel environment, whereas most mice responded adequately with an increase of ACh release upon infusion of scopolamine. A strong reduction of scopolamine-mediated ACh release was seen after amyloid Aß42 peptide was administered into the hippocampus of tau-transgenic mice. Choline acetyltransferase activities were unchanged in tau-transgenic mice but acetylcholinesterase activities were increased in thalamus. Lactate and choline levels were increased in tau-transgenic mice but high-affinity choline uptake was slightly reduced. Our data suggest that even mild to moderate tau pathology in JNPL3 mice is able to depress cholinergic transmission in brain regions that receive input from the basal forebrain via long projection neurons. This impairment may be reinforced by amyloid peptide formation.

Effects of Ginkgo biloba Extract EGb 761, Donepezil and their Combination on Central Cholinergic Function in Aged Rats.

PURPOSE: Ginkgo extract EGb 761 and cholinesterase inhibitors have been shown to be effective in the treatment of dementia patients. In addition to neuroprotective effects, Ginkgo extract EGb 761 has been reported to elevate brain levels of certain neurotransmitters such as dopamine, noradrenaline, and acetylcholine. In the present study, we investigated the impact of EGb 761, donepezil and the combination of both drugs on the central cholinergic system in aged rats. METHODS: 24 month old rats received EGb 761 (100 mg/kg/day), donepezil (1.5 mg/kg/day), the combination of both drugs or vehicle control by oral gavage for 14 days. We used microdialysis in rat hippocampus to monitor extracellular concentrations of acetylcholine (ACh), choline, glucose and lactate. Brain homogenates were prepared to measure activities of acetylcholinesterase (AChE), choline acetyltransferase (ChAT) and high affinity choline uptake (HACU). RESULTS: While EGb 761 alone had no effect, donepezil and the combination of donepezil and EGb 761 increased basal ACh levels by 2- to 3-fold. Concomitantly, significant reductions of AChE and HACU were measured in both groups. No differences were seen between donepezil and the combination in these parameters. Treatment with EGb 761 decreased extracellular choline release and showed a tendency to moderately elevate ChAT activity. CONCLUSIONS: We found that donepezil and EGb 761 do not display a pharmacological interaction when given together. Adding EGb 761 did not modify the effects of donepezil on the hippocampal cholinergic system. Reduced choline levels indicate neuroprotective properties of EGb 761. Therefore, the combination of EGb 761 and donepezil may be beneficial in the treatment of Alzheimer's disease (AD). This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.