Fig. 3.

Hippocampal circuits involved in AD and strategies for targeted manipulations. A Topographical dissemination of Aβ and tau pathologies in AD. Tau aggregates develop in the locus coeruleus (LC), and last in broad areas of the neocortex (NC). In contrast to tau pathology, amyloid-β deposits in AD are first observed in the NC and then in basal ganglia structures and the brainstem. B During AD progression, projections from other brain regions to the hippocampus undergo distinct alterations. Targeting those inputs may rescue spatial memory deficits in AD. C Schematic showing gradual changes of different synaptic inputs onto a CA1 pyramidal neuron across different stages of AD. Entorhinal cortex (EC) and CA3 are two major excitatory inputs, while PV and SST are two main inhibitory inputs to the CA1 pyramidal neuron. Compared with healthy brain, CA1 pyramidal neurons may become hyperactive due to a combination of decreased inhibition as well as an increase in excitation (↑E/I) during the early stages of AD. Then, during the later stages, aggressive Aβ and tau pathologies may affect synapses globally, resulting in hypoactivity (↓E/I). Targeting E/I imbalance may rescue spatial memory deficits in AD. D Stimulating engram cells in the hippocampus may improve memory retrieval in AD.