Protein oligomerization and aggregation are key events in age-related neurodegenerative disorders, causing neuronal disturbances including microtubule destabilization, transport failure and loss of synaptic integrity that precede cell death. The abnormal buildup of proteins can overload digestive systems and this, in turn, activates lysosomes in different disease states and stimulates the inducible class of lysosomal protein degradation, macroautophagy. These responses were studied in a hippocampal slice model well known for amyloidogenic species, tau aggregates, and ubiquitinated proteins in response to chloroquine-mediated disruption of degradative processes. Chloroquine was found to cause a pronounced appearance of prelysosomal autophagic vacuoles in pyramidal neurons. The vacuoles and dense bodies were concentrated in the basal pole of neurons and in dystrophic neurites. In hippocampal slice cultures treated with Abeta(142), ultrastructural changes were also induced. Autophagic responses may be an attempt to compensate for protein accumulation, however, they were not sufficient to prevent axonopathy indicated by swellings, transport deficits, and reduced expression of synaptic components. Additional chloroquine effects included activation of cathepsin D and other lysosomal hydrolases. Abeta(142) produced similar lysosomal activation, and the effects of Abeta(142) and chloroquine were not additive, suggesting a common mechanism. Activated levels of cathepsin D were enhanced with the lysosomal modulator Z-Phe-Ala-diazomethylketone (PADK). PADK-mediated lysosomal enhancement corresponded with the restoration of synaptic markers, in association with stabilization of microtubules and transport capability. To show that PADK can modulate the lysosomal system in vivo, IP injections were administered over a 5-day period, resulting in a dose-dependent increase in lysosomal hydrolases. The findings indicate that degradative responses can be modulated to promote synaptic maintenance.
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.
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