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The functional significance of soluble amyloid beta (Abeta) oligomers for learning and memory deficits in Alzheimer's disease

Final Report Summary - ABETACOGNITION (The functional significance of soluble amyloid beta (Abeta) oligomers for learning and memory deficits in Alzheimer's disease)

Alzheimer’s disease (AD) is characterised by a gradual cognitive decline, which initially affects learning, memory and attention, and gradually impairs other cognitive and emotional functions, culminating in a complete cognitive breakdown. The cause and pathogenesis of the disease in aging patients are still largely unknown, mainly because of the difficulties to study cellular brain pathology in living humans. Recent in vitro studies suggest that the depotentiation or degradation of synapses by soluble amyloid β-peptide (Aβ) oligomers might play a role in mediating the progression of the disease. However, what is lacking is a translational approach that establishes the links between these cellular pathologies observed in vitro, and the gradual cognitive decline. The aim of this project is to gain novel insights into whether and how soluble Aβ oligomers may interfere with cognitive ability and neural activity in a living organism, and whether these processes can be reversed by pharmacological intervention. Specifically, we wished to address whether abundant Aβ oligomers cause cognitive deficits similar to those observed in early AD (objective 1), whether and how high concentration of Aβ oligomers affect neural network activity in brain regions compromised early in AD (objective 2), and whether the inhibition of signalling elements mediating established Aβ-induced synaptic changes can reverse Aβ oligomer-induced cognitive deficits (objective 3).
Key to the project were mice which carry human APP with the Swedish (K670N;M671L) and the Arctic (E693G) mutation (arcAβ mice). The mutated form of APP is less prone to aggregate, which results in abundant intraneuronal Aβ oligomer deposits in the hippocampus and cortex of arcAβ mice aged > 3 months, whereas large extracellular β-amyloid plaques only becoming evident > 9 month. In order to address whether Aβ oligomers may be causal for cognitive deficits observed in early AD, such as memory, attention and response inhibition (Objective 1), we assessed 3 and 6 month old arcAβ mice on an object recognition paradigm requiring the perirhinal cortex and the hippocampus; and on a series of automated, touchscreen-operated behavioural tasks requiring prefrontal cortex function (5-choice Serial Reaction Time Task and Visual Discimination and Reversal Learning). In order to gain insights into Aβ-oligomer mediated neural changes that maybe responsible for AD-related cognitive deficits (Objective 2), we recorded the brain activity of 6 month-old arcAβ mice and wild type littermate controls with intracranial EEG and EMG. In a series of pharmacological studies, we assessed whether Aβ-oligomer-mediated changes in excitation or inhibition were responsible for cognitive deficits and alterations in network activity (Objective 3). Several cohorts of 6-month old arcAβ-mice and wild type controls were implanted with cannulae positioned in the perirhinal cortex. 1h before behavioural testing on an object recognition paradigm, mice received acute injections of either memantine (NMDA-receptor antagonist), tiagabine (GABA-agonist), or low-dose picrotoxin (GABA-agonist). In parallel experiments, we addressed whether and how these pharmacological interventions altered neural activity represented in the EEG.
We detected abundant Aβ-oligomers in 6 month-old arcAβ mice, and found that these animals had significant object recognition memory and attention deficits. The outcome of the behavioural experiments suggested that high concentrations of Aβ-oligomers, as they also occur during early AD in humans, compromise the function of perirhinal cortex and prefrontal cortex. In order to gain insights into the neural substrates responsible for these deficits, we compared long-term (24 h) EEG of 6 month old arcAβ mice and wild type mice. We found significantly higher overall activity in arcAβ mice, and preliminary spectral analysis indicated reduced delta (0.5-5 Hz) and enhanced theta (5-9 Hz) power. Reduction of excitation by systemic administration of memantine, a partial NMDA-receptor antagonist often prescribed for AD-patients, significantly reduced EEG power in both genotypes, and reversed the enhancemend of theta power in arcAβ mice, but had no effect on delta frequencies. The physiological effects of memantine were paralleled by striking behavioural consequences: acute injections of memantine into the perirhinal cortex completely rescued the object recognition impairment of Aβ-mice, without affecting wild type performance. In a further set of experiments, we aimed to address whether reduction of excitation by GABA-agonists had a similar effect. However, acute perirhinal injections of tiagabine impaired object recognition in wild type mice, and did not improve performance of arcAβ animals. In an attempt to dissect the role that enhanced excitation plays for cognitive performance, we (further) enhanced excitation in wild type and arcAβ mice by intra-perirhinal injection of low-dose picrotoxin, a GABA-antagonist. However, the treatment had non-specific effects on locomotion and motivation, which made conclusive behavioural testing impossible.

Taken together, our findings provide evidence that pre-plaque Aβ-oligomers, as they occur in early stages of AD, can play a significant role in the development of memory and attention deficits. We were also able to show that Aβ-oligomers cause neural changes reflected in an altered EEG in vivo, which can partially be reversed by pharmacological intervention. Furthermore, we provide initial insights into how memantine, a drug long used for the symptomatic treatment of AD, may exert its cognition-enhancing effects. Our results contribute to the search for new drug targets to prevent or retard the progression of AD during early stages of disease onset, which will not only reduce suffering but will also reduce the financial burden imposed upon European countries by the cost of the care and medical treatment of AD patients. Moreover, although not fully recapitulating the profile of AD patients, the observed EEG changes in arcAβ mice suggest that EEG is a sensitive and translational biomarker in murine models, which will facilitate translational AD-research within the EU and world wide, contributing to European competitiveness.