nSMase2 Inhibitor DPTIP Rescues Synaptic Density in APPswe/PS1deltaE9 Mice

In_Vivo Score: 0.803 Price: $0.50 Alzheimer's disease APPswe/PS1dE9 bigenic mice, 6-9 months (n=12/group x 3: WT-vehicle, APP-vehicle, APP-DPTIP) Status: proposed

What This Experiment Tests

In_Vivo experiment designed to assess clinical efficacy targeting SMPD3 in APPswe/PS1dE9 bigenic mice, 6-9 months (n=12/group x 3: WT-vehicle, APP-vehicle, APP-DPTIP). Primary outcome: Synaptic density (PSD-95 puncta/um2) maintained at WT levels (+-15%); MWM latency <=120 s

Description

Test whether chronic DPTIP (selective nSMase2 inhibitor, 10 mg/kg i.p. daily) preserves synaptic density, reduces ceramide-driven exosome secretion, and improves spatial memory in 6-month APPswe/PS1dE9 mice over a 3-month treatment window.

TARGET GENE

SMPD3

MODEL SYSTEM

APPswe/PS1dE9 bigenic mice, 6-9 months (n=12/group x 3: WT-vehicle, APP-vehicle, APP-DPTIP)

ESTIMATED COST

$62,000

TIMELINE

14 months

PATHWAY

SMPD3 -> ceramide -> exosome biogenesis -> synaptic loss

SOURCE

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

PRIMARY OUTCOME

Synaptic density (PSD-95 puncta/um2) maintained at WT levels (+-15%); MWM latency <=120 s

Scoring Dimensions

Protocol

Treat APP/PS1 mice with DPTIP (10 mg/kg i.p., daily) or vehicle for 12 weeks (6-9 months). 2. Weekly body weight, open field for tolerability. 3. Morris Water Maze at 9 months (4 days acquisition, 1 probe trial). 4. Harvest cortex/hippocampus: lipidomics (ceramide species by LC-MS/MS), western blot (PSD-95, synapsin), Golgi-staining spine density, nanoparticle tracking for exosome count and size. 5. IHC: Abeta plaque burden (6E10), synaptophysin puncta. 6. Primary: PSD-95 western (ratio to GAPDH); secondary: Cer16:0, MWM, exosome count.

Expected Outcomes

DPTIP will reduce ceramide Cer16:0 by >=60%, cut exosome secretion by >=40%, restore PSD-95 to within 15% of WT, and reduce MWM escape latency by >=30%.

Success Criteria

Primary: PSD-95 restoration >=80% of WT level (one-way ANOVA p<0.05). Secondary: Cer16:0 reduction >=50%; MWM probe trial platform crosses >=3 (vs <1 in vehicle).

Related Hypotheses (2)

Neutral Sphingomyelinase-2 Inhibition for Synaptic Protection in Neurodegeneration0.844

Selective Neutral Sphingomyelinase-2 Inhibition Therapy0.731

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