Hippocampal neural circuit mechanisms in Alzheimer's disease revealed by viral-genetic circuit mapping - PubMed (original) (raw)

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Hippocampal neural circuit mechanisms in Alzheimer's disease revealed by viral-genetic circuit mapping

Qiao Ye et al. Neurobiol Dis. 2025 Nov.

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with growing major health impacts in countries with aging populations. Existing therapeutic approaches that have been based on neurochemical and neuropathological findings are largely ineffective. This lack of progress suggests we require a new framework for future AD therapies. The examination of neural circuit mechanisms in AD mouse models is an emerging focus for identifying new AD treatment strategies. We now know there are neural circuit-level maladaptive alterations in AD brains, some of which appear very early in the disease process before neuropathological features are detectable. Recent advancements in viral-genetic technologies allow us to quantitatively map the cell-type-specific neural circuit connections in AD mouse models. Monosynaptic rabies virus mapping reveals age-progressive changes in both long-range and local hippocampal neural circuit connectivity in AD mouse models - and provides explanations for human AD behavioral defects, such as sex differences and higher level visual deficits. These recent developments in neural circuits level concepts and technology present new opportunities for studying AD pathogenesis for early identification of the disease and for developing novel therapeutic interventions.

Keywords: Alzheimer's disease; Neural circuit tracing; Rabies; Viral-genetic tools.

Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

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Conflict of interest statement

Declaration of competing interest The authors declare no competing interests.

Figures

Fig. 1

Fig. 1. Circuit mapping of synaptic connectivity to CA1 excitatory neurons in APP-KI mouse

A, Injection schematics for monosynaptic rabies tracing of CA1 excitatory neurons in APP-KI or WT mice. Mice were injected with helper AAV, followed by rabies virus injection at CA1 pyramidal layer. Lower panels are representative presynaptic input regions. B, Example fluorescent coronal images of APP-KI mouse brain, including CA1 injection sites, and presynaptic input areas. AAV is represented by green, rabies is labeled red. The slices are counterstained with DAPI. The scale bar represents 50 μm. Figure modified from Ye et al., 2022.

Fig. 2

Fig. 2. Circuit mapping of synaptic connectivity to SUB excitatory neurons in 5xFAD mouse

A, Brain-wide presynaptic inputs of SUB excitatory neurons in 5xFAD mice based on injection in the SUB followed by circuit labeling along the anterior to posterior axis, showing widespread labeling of multiple brain regions. Both AAV and rabies virus were injected at dorsal SUB. B, Example fluorescent coronal images of 5xFAD mouse brain, including SUB injection sites, and presynaptic input areas. AAV is labeled green, and rabies virus is labeled red. The slices are counterstained with DAPI. The scale bar represents 200 μm. C, Connectivity strength index (CSI) comparisons of example input regions over young WT mice, middle-age WT mice, young 5xFAD mice, and middle-age 5xFAD mice. Statistical significance levels are denoted by * p ≤ 0.05, ** p ≤ 0.01, *** p ≤ 0.001, **** p ≤ 0.0001. Figure modified from Ye et al., 2024.

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