title: Hippocampal endosomal, lysosomal, and autophagic dysregulation in mild cognitive impairment: correlation with aβ and tau pathology.
abstract: Endosomal-lysosomal and autophagic dysregulation occurs in the hippocampus in prodromal Alzheimer disease (AD), but its relationship with β-amyloid (Aβ) and tau pathology remains unclear. To investigate this issue, we performed immunoblot analysis of hippocampal homogenates from cases with an antemortem clinical diagnosis of no cognitive impairment, mild cognitive impairment (MCI), and AD. Western blot analysis revealed significant increases in the acid hydrolase cathepsin D and early endosome marker rabaptin5 in the MCI group compared with AD, whereas levels of phosphorylated mammalian target of rapamycin proteins (pmTOR), total mammalian target of rapamycin (mTOR), p62, traf6, and LilrB2 were comparable across clinical groups. Hippocampal Aβ1-40 and Aβ1-42 concentrations and AT8-immunopositive neurofibrillary tangle density were not significantly different across the clinical groups. Greater cathepsin D expression was associated with global cognitive score and episodic memory score but not with mini mental state examination or advanced neuropathology criteria. These results indicate that alterations in hippocampal endosomal-lysosomal proteins in MCI are independent of tau or Aβ pathology.
authors.affiliation: From the Department Neurological Science, Rush University Medical Center, Chicago, Illinois (SEP, EJM); Alzheimer's Disease Research Laboratory, Barrow Neurological Institute, Phoenix, Arizona (BH, MN, EJM); Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida (JW); Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York (SDG); and Departments of Psychiatry, Physiology and Neuroscience, NYU Langone Medical Center, New York (SDG), New York; and Departments of Neurology and Psychiatry, University of Pittsburgh and Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania (MDI).
authors.forename: Sylvia E
authors.initials: SE
authors.lastname: Perez
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.forename: Muhammad
authors.initials: M
authors.lastname: Nadeem
authors.forename: Joanne
authors.initials: J
authors.lastname: Wuu
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Ginsberg
authors.forename: Milos D
authors.initials: MD
authors.lastname: Ikonomovic
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Mufson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D001343:Autophagy / Q000502:physiology; D060825:Cognitive Dysfunction / Q000378:metabolism* / Q000473:pathology; D015331:Cohort Studies; D011992:Endosomes / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010446:Peptide Fragments / Q000096:biosynthesis; D016875:tau Proteins / Q000096:biosynthesis*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins