Closed-loop tFUS Enhances Glymphatic Clearance and Restores CA1 PV Interneuron Gamma in APP/PS1 Mice

In_Vivo Score: 0.765 Price: $0.50 Alzheimer's disease APP/PS1 mice 8-11 months (n=10/group x 3 groups) with hippocampal LFP implants; MRI-guided tFUS Status: proposed

What This Experiment Tests

In_Vivo experiment designed to assess clinical efficacy targeting PVALB in APP/PS1 mice 8-11 months (n=10/group x 3 groups) with hippocampal LFP implants; MRI-guided tFUS. Primary outcome: Perivascular Abeta load around PV+ cells reduced >=35%; CA1 gamma power restored to >=70% of WT

Description

Test whether closed-loop tFUS (focused on dorsal hippocampus, 250 kHz, 2 Hz pulsed ISI phase-locked to slow oscillation) enhances AQP4-dependent glymphatic CSF influx, reduces perivascular Abeta load around PV+ interneurons, and restores CA1 gamma oscillation power in APP/PS1 mice.

TARGET GENE

PVALB (Score: 0.335)

MODEL SYSTEM

APP/PS1 mice 8-11 months (n=10/group x 3 groups) with hippocampal LFP implants; MRI-guided tFUS

ESTIMATED COST

$125,000

TIMELINE

20 months

PATHWAY

Glymphatic AQP4 -> perivascular Abeta clearance -> PV interneuron perisomatic inhibition -> gamma oscillation

SOURCE

task:a989715e-c687-4558-91ca-74fce1474bd2

PRIMARY OUTCOME

Perivascular Abeta load around PV+ cells reduced >=35%; CA1 gamma power restored to >=70% of WT

Scoring Dimensions

Protocol

APP/PS1 mice, 8 months, MRI-guided tFUS targeting dorsal CA1. 2. Closed-loop: slow-oscillation (0.5-1 Hz) detection -> tFUS pulse at up-state onset (250 kHz, 0.25 MPa, 200 ms duration, 2 Hz PRF) for 1 h during NREM (head-fixed). 3. 30 daily sessions; controls: sham-tFUS, WT-tFUS. 4. Endpoints: - MRI T1 with gadolinium intrathecal for glymphatic influx (CSF tracer distribution) - IHC: AQP4 polarisation (aquaporin-4 end-feet), PV+/Abeta co-staining, plaque load - LFP power spectral density (30-80 Hz gamma power in CA1) - Contextual fear conditioning, Barnes maze - Safety: GFAP reactivity, NeuN counts, MRI T2. 5. Primary: PV perisomatic Abeta area fraction; secondary: CA1 gamma power, glymphatic influx.

Expected Outcomes

tFUS will increase glymphatic influx 2x (gadolinium signal), reduce PV-soma-adjacent Abeta >=35%, restore CA1 gamma >=70% WT, and improve Barnes maze latency.

Success Criteria

Primary: PV perisomatic Abeta area fraction reduced >=35% vs APP/PS1-sham (p<0.05). Secondary: CA1 gamma power >=70% of WT level; no T2 lesions on MRI.

Related Hypotheses (6)

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