Lysosomal Enhancement Promotes Synaptic Integrity and Functional Recovery in Mouse Models of Alzheimer's Disease

Abstract

Reducing protein accumulation is essential for treating Alzheimer's disease (AD) by attenuating a pathogenic cascade that leads to synaptic decline. Z‐Phe‐Ala‐diazomethylketone (PADK) increases lysosomal enzymes 2‐ to 9‐fold in vitro and in vivo. This enhancement clears AD‐related proteins and restores synaptic integrity. Here, PADK produced a dose‐dependent increase in cathepsin D without adverse effects. In the first of two transgenic models of AD, APPSwInd mice of 10–11 months exhibited deficits in coordination and spatial memory. PADK at 23 mg/kg × 9 d recovered open‐field intersession habituation (p<0.03) and improved balance beam and rotarod scores in the mice (p<0.001). 6E10 anti‐Aβ staining also revealed a 39% reduction in hippocampal CA1 sp. In a second model, 18–20‐month old APPswe/PS1dE9 mice exhibited a deficit in episodic spontaneous alternation behavior (SAB). PADK at 20 mg/kg × 10 d improved their SAB to control‐level (p=0.01). Synaptic markers GluR1 and NCAM180 were decreased 23–34% in APPswe/PS1dE9 hippocampus compared to non‐tg mice. Corresponding with the SAB improvement, PADK increased GluR1 and NCAM to non‐tg levels (p=0.0001–0.002). PADK also reduced 6E10 staining of CA1 neurons as well as number and size of plaque structures. Lysosomal modulatory drugs that enhance clearance mechanisms thus have the potential to slow the synaptic decline and cognitive deficits associated with AD.