Illuminating Neural Circuits in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder and there is currently no cure. Neural circuit dysfunction is the fundamental mechanism underlying the learning and memory deficits in patients with AD. Therefore, it is important to understand the structural features and mechanisms underlying the deregulated circuits during AD progression, by which new tools for intervention can be developed. Here, we briefly summarize the most recently established cutting-edge experimental approaches and key techniques that enable neural circuit tracing and manipulation of their activity. We also discuss the advantages and limitations of these approaches. Finally, we review the applications of these techniques in the discovery of circuit mechanisms underlying β-amyloid and tau pathologies during AD progression, and as well as the strategies for targeted AD treatments.

Keywords: Alzheimer’s disease; Chemogenetics; Neural circuit; Neural circuit tracing; Optogenetics; Single cell RNA sequencing.

Fig. 1

Schematic of cTRIO for neural circuit tracing. In X-Cre mice, CAV2-DIO-Flp is injected into region C, while AAV-fDIO-TVA/G and EnvA-RV-ΔG are injected into region B. Only the presynaptic inputs to neurons that are located in region B, project to region C, and express geneX (orange cell in region B) will be retrogradely labelled by RV (green cell in region A) (A → B^X+ → C). However, presynaptic inputs to region B neurons that innervate region C but do not express gene X (grey cell in region D) (D → B^X− → C), or region B cells that do not project to region C (B → E) will not be labeled.

Fig. 2

Schematics of neural manipulation by optogenetics and chemogenetics. A, B Upon light stimulation, Na⁺ and Ca²⁺ move down their electrochemical gradients on the ChR2-expressing neurons and depolarize the membrane, resulting in neuron excitation. While hyperpolarizing current on NpHR-, Arch- or mutated ChR2-expressing neurons leads to neuron inhibition. C, D In the presence of CNO, hM3Dq-expressing neurons are activated, while hM4Di-expressing neurons are inhibited via changing the concentration of second messengers.

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.