Abstract
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.
Highlights
Lysosomes, with their content of several classes of hydrolases, play a vital role in protein and glycoconjugate clearance for maintaining cellular homeostasis
To assess protein accumulation pathology related to Alzheimer’s disease (AD), immunostaining procedures were applied to brain tissue from amyloid precursor protein/presenilin-1 (APP/PS1) mice that express mutant forms of APP and presenilin-1 and exhibit progressive amyloid deposition and neuritic abnormalities [31]
Central nervous system (CNS) safety was further evaluated in middle-aged mice treated with 0–40 mg/kg PADK for nine days, with the manifold lysosomal modulation plateauing at near 25 mg/kg, far below the 250–500 mg/kg range for other indications
Summary
With their content of several classes of hydrolases, play a vital role in protein and glycoconjugate clearance for maintaining cellular homeostasis. CatB upregulation events were found in response to the buildup of Aβ and related peptides [13,16], to huntingtin accumulation [17], and to the inhibition of protein clearing pathways [18,19] Such response capability is likely involved in the increased number of lysosomes containing high levels of CatB in the at-risk neuronal populations of sporadic AD [20]. This potential compensatory response may explain the slow progression of AD that often occurs, as well as the AD proteinopathy that begins many years before cognitive symptoms become apparent [21]. The CatB proteolytic responses support early and prolonged signaling events that work to maintain proteostasis and reduce pathogenic protein deposition and, when effective, they perhaps explain the extended nature of AD in many individuals
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