title: Protective effects of positive lysosomal modulation in Alzheimer's disease transgenic mouse models.
abstract: Alzheimer's disease (AD) is an age-related neurodegenerative pathology in which defects in proteolytic clearance of amyloid β peptide (Aβ) likely contribute to the progressive nature of the disorder. Lysosomal proteases of the cathepsin family exhibit up-regulation in response to accumulating proteins including Aβ(1-42). Here, the lysosomal modulator Z-Phe-Ala-diazomethylketone (PADK) was used to test whether proteolytic activity can be enhanced to reduce the accumulation events in AD mouse models expressing different levels of Aβ pathology. Systemic PADK injections in APP(SwInd) and APPswe/PS1ΔE9 mice caused 3- to 8-fold increases in cathepsin B protein levels and 3- to 10-fold increases in the enzyme's activity in lysosomal fractions, while neprilysin and insulin-degrading enzyme remained unchanged. Biochemical analyses indicated the modulation predominantly targeted the active mature forms of cathepsin B and markedly changed Rab proteins but not LAMP1, suggesting the involvement of enhanced trafficking. The modulated lysosomal system led to reductions in both Aβ immunostaining as well as Aβ(x-42) sandwich ELISA measures in APP(SwInd) mice of 10-11 months. More extensive Aβ deposition in 20-22-month APPswe/PS1ΔE9 mice was also reduced by PADK. Selective ELISAs found that a corresponding production of the less pathogenic Aβ(1-38) occurs as Aβ(1-42) levels decrease in the mouse models, indicating that PADK treatment leads to Aβ truncation. Associated with Aβ clearance was the elimination of behavioral and synaptic protein deficits evident in the two transgenic models. These findings indicate that pharmacologically-controlled lysosomal modulation reduces Aβ(1-42) accumulation, possibly through intracellular truncation that also influences extracellular deposition, and in turn offsets the defects in synaptic composition and cognitive functions. The selective modulation promotes clearance at different levels of Aβ pathology and provides proof-of-principle for small molecule therapeutic development for AD and possibly other protein accumulation disorders.
authors.affiliation: Neurosciences Program, University of Connecticut, Storrs, Connecticut, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Butler
authors.forename: Jeannie
authors.initials: J
authors.lastname: Hwang
authors.forename: Candice
authors.initials: C
authors.lastname: Estick
authors.forename: Akiko
authors.initials: A
authors.lastname: Nishiyama
authors.forename: Saranya Santhosh
authors.initials: SS
authors.lastname: Kumar
authors.forename: Clive
authors.initials: C
authors.lastname: Baveghems
authors.forename: Hollie B
authors.initials: HB
authors.lastname: Young-Oxendine
authors.forename: Meagan L
authors.initials: ML
authors.lastname: Wisniewski
authors.forename: Ana
authors.initials: A
authors.lastname: Charalambides
authors.forename: Ben A
authors.initials: BA
authors.lastname: Bahr
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007659:Ketones / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D007659:Ketones; D010446:Peptide Fragments; D020011:Protective Agents; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D002401:Cathepsin B; D002402:Cathepsin D; D020691:rab GTP-Binding Proteins