Characterization of hippocampal amyloidosis induced by amyloid‐ β in behaving mice: Developing topics

Background In early stages of Alzheimer’s disease, disruption of learning and memory processes that rely on hippocampal performance correlates with aberrant patterns of synchronous neuronal activity that arise prior to evident neurodegeneration. These disturbances emerge as a result of neuronal hyperexcitability and synaptic dysfunction induced by soluble forms of amyloid‐ β (A β ) peptide, which trigger an imbalance between excitatory and inhibitory neurotransmission systems. The molecular mechanisms underlying these alterations remain unclear but functional evidence points to alteration of neuronal excitability playing a pivotal role in early A β ‐induced AD pathogenesis. Although A β 1‐42 and A β 1‐40 are widely known for their clinical relevance, A β 25‐35 has been proposed as the biologically active fragment. In contrast to other A β isoforms, A β 25‐35 does not generate ion‐permeable pores in neuronal membrane, but it has been shown to induce major neuropathological signs related to early AD stages. Hence, it has been extensively used to study the pathophysiological events related to A β ‐induced neuronal dysfunction. It remains to be explored, however, whether A β 25‐35 mimics the neurotoxic effects on the hippocampus exhibited by other clinically relevant species such as A β 1‐42 (Sánchez‐Rodriguez et al., 2017, 2019, 2020). Methods Here, we systematically characterized the effects of A β 25‐35 on hippocampal function at different —behavior, networks and synapses— levels of complexity in behaving mice prepared for chronic intracerebroventricular injections. Likewise, animals were implanted with electrodes for in vivo recordings at the hippocampal CA1 area and electrical stimulation of the Schaffer collateral pathway. Results Our data showed evident learning and memory impairments in hippocampal‐dependent tasks such as novel object recognition and open field habituation tests. Underlying these deficits, local field potential (LFP) recordings revealed an altered oscillatory activity. Additionally, theta and gamma rhythms, crucially involved in successful memory encoding, were abnormally increased. Lastly, we also found impairments in long‐term synaptic plasticity at the CA3‐CA1 synapse, where A β 25‐35 transformed long‐term potentiation (LTP) into long‐term depression (LTD). Conclusions Taken together, these results support the notion that A β 25‐35 ‐mediated effects on synaptic properties and neural network activity mimicked those exerted by A β 1‐42 . Thus, we verified the potentiality of the A β 25‐35 peptide to study the hippocampal pathophysiology of early amyloidosis.