Many neurodegenerative disorders have lysosomal impediments, and the list of proposed treatments targeting lysosomes is growing. We investigated the role of lysosomes in Alzheimer’s disease (AD) and other age-related disorders, as well as in a strategy to compensate for lysosomal disturbances. Comprehensive immunostaining was used to analyze brains from wild-type mice vs. amyloid precursor protein/presenilin-1 (APP/PS1) mice that express mutant proteins linked to familial AD. Also, lysosomal modulation was evaluated for inducing synaptic and behavioral improvements in transgenic models of AD and Parkinson’s disease, and in models of mild cognitive impairment (MCI). Amyloid plaques were surrounded by swollen organelles positive for the lysosome-associated membrane protein 1 (LAMP1) in the APP/PS1 cortex and hippocampus, regions with robust synaptic deterioration. Within neurons, lysosomes contain the amyloid β 42 (Aβ42) degradation product Aβ38, and this indicator of Aβ42 detoxification was augmented by Z-Phe-Ala-diazomethylketone (PADK; also known as ZFAD) as it enhanced the lysosomal hydrolase cathepsin B (CatB). PADK promoted Aβ42 colocalization with CatB in lysosomes that formed clusters in neurons, while reducing Aβ deposits as well. PADK also reduced amyloidogenic peptides and α-synuclein in correspondence with restored synaptic markers, and both synaptic and cognitive measures were improved in the APP/PS1 and MCI models. These findings indicate that lysosomal perturbation contributes to synaptic and cognitive decay, whereas safely enhancing protein clearance through modulated CatB ameliorates the compromised synapses and cognition, thus supporting early CatB upregulation as a disease-modifying therapy that may also slow the MCI to dementia continuum.
Cysteine protease inhibitors have long been part of drug discovery programs for Alzheimer’s disease (AD), traumatic brain injury (TBI), and other disorders. Select inhibitors reduce accumulating proteins and AD pathology in mouse models. One such compound, Z-Phe-Aladiazomethylketone (PADK), exhibits a very weak IC50 (9–11 μM) towards cathepsin B (CatB), but curiously PADK causes marked up-regulation of the Aβ-degrading CatB and improves spatial memory. Potential therapeutic and weak inhibitor E64d (14 μM IC50) also up-regulates CatB. PADK and E64d were compared regarding the blockage of calcium-induced cytoskeletal deterioration in brain samples, monitoring the 150-kDa spectrin breakdown product (SBDP) known to be produced by calpain. PADK had little to no effect on SBDP production at 10–100 μM. In contrast, E64d caused a dose-dependent decline in SBDP levels with an IC50 of 3–6 μM, closely matching its reported potency for inhibiting μ-calpain. Calpain also cleaves the cytoskeletal organizing protein gephyrin, producing 49-kDa (GnBDP49) and 18-kDa (GnBDP18) breakdown products. PADK had no apparent effect on calcium-induced gephyrin fragments whereas E64d blocked their production. E64d also protected the parent gephyrin in correspondence with reduced BDP levels. The findings of this study indicate that PADK’s positive and selective effects on CatB are consistent with human studies showing exercise elevates CatB and such elevation correlates with improved memory. On the other hand, E64d exhibits both marginal CatB enhancement and potent calpain inhibition. This dual effect may be beneficial for treating AD. Alternatively, the potent action on calpain-related pathology may explain E64d’s protection in AD and TBI models.
Heat shock proteins (HSPs) are a family of molecular chaperones that regulate essential protein refolding and triage decisions to maintain protein homeostasis. Numerous co-chaperone proteins directly interact and modify the function of HSPs, and these interactions impact the outcome of protein triage, impacting everything from structural proteins to cell signaling mediators. The chaperone/co-chaperone machinery protects against various stressors to ensure cellular function in the face of stress. However, coding mutations, expression changes, and post-translational modifications of the chaperone/co-chaperone machinery can alter the cellular stress response. Importantly, these dysfunctions appear to contribute to numerous human diseases. Therapeutic targeting of chaperones is an attractive but challenging approach due to the vast functions of HSPs, likely contributing to the off-target effects of these therapies. Current efforts focus on targeting co-chaperones to develop precise treatments for numerous diseases caused by defects in protein quality control. This review focuses on the recent developments regarding selected HSP70/HSP90 co-chaperones, with a concentration on cardioprotection, neuroprotection, cancer, and autoimmune diseases. We also discuss therapeutic approaches that highlight both the utility and challenges of targeting co-chaperones.
Heat shock proteins (HSPs) are a family of molecular chaperones that regulate essential protein refolding and triage decisions to maintaining protein homeostasis. Numerous co-chaperone proteins directly interact and modify the function of HSPs, and these interactions impact the outcome of protein triage, impacting everything from structural proteins to cell signaling mediators. The chaperone/co-chaperone machinery protects against various stressors to ensuring cellular function in the face of stress. However, coding mutations, expression changes, and post-translational modifications of the chaperone/co-chaperone machinery can alter the cellular stress response. Importantly, these dysfunctions appear to contribute to numerous human diseases. Therapeutic targeting of chaperones is an attractive but challenging approach due to the vast functions of HSPs, likely contributing to the off-target effects of these therapies. Current efforts focus on targeting co-chaperones to develop precise treatments for numerous diseases caused by defects in protein quality control. This review focuses on the recent developments regarding selected HSP70/HSP90 co-chaperones, focusing on cardioprotection, neuroprotection, and cancer. We also discuss therapeutic approaches that highlight both the utility and challenges of targeting co-chaperones.
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