title: Telomere shortening reduces Alzheimer's disease amyloid pathology in mice.
abstract: Alzheimer's disease is a neurodegenerative disorder of the elderly and advancing age is the major risk factor for Alzheimer's disease development. Telomere shortening represents one of the molecular causes of ageing that limits the proliferative capacity of cells, including neural stem cells. Studies on telomere lengths in patients with Alzheimer's disease have revealed contrary results and the functional role of telomere shortening on brain ageing and Alzheimer's disease is not known. Here, we have investigated the effects of telomere shortening on adult neurogenesis and Alzheimer's disease progression in mice. The study shows that aged telomerase knockout mice with short telomeres (G3Terc-/-) exhibit reduced dentate gyrus neurogenesis and loss of neurons in hippocampus and frontal cortex, associated with short-term memory deficit in comparison to mice with long telomere reserves (Terc+/+). In contrast, telomere shortening improved the spatial learning ability of ageing APP23 transgenic mice, a mouse model for Alzheimer's disease. Telomere shortening was also associated with an activation of microglia in ageing amyloid-free brain. However, in APP23 transgenic mice, telomere shortening reduced both amyloid plaque pathology and reactive microgliosis. Together, these results provide the first experimental evidence that telomere shortening, despite impairing adult neurogenesis and maintenance of post-mitotic neurons, can slow down the progression of amyloid plaque pathology in Alzheimer's disease, possibly involving telomere-dependent effects on microglia activation.
authors.affiliation: Department of Molecular Medicine and Max-Planck-Research Department for Stem Cell Aging, University of Ulm, D-89081 Ulm, Germany.
authors.forename: Harshvardhan
authors.initials: H
authors.lastname: Rolyan
authors.forename: Annika
authors.initials: A
authors.lastname: Scheffold
authors.forename: Annette
authors.initials: A
authors.lastname: Heinrich
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Begus-Nahrmann
authors.forename: Britta Heike
authors.initials: BH
authors.lastname: Langkopf
authors.forename: Sabine M
authors.initials: SM
authors.lastname: Hölter
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Vogt-Weisenhorn
authors.forename: Birgit
authors.initials: B
authors.lastname: Liss
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Dieter Chichung
authors.initials: DC
authors.lastname: Lie
authors.forename: Dietmar Rudolf
authors.initials: DR
authors.lastname: Thal
authors.forename: Knut
authors.initials: K
authors.lastname: Biber
authors.forename: Karl Lenhard
authors.initials: KL
authors.lastname: Rudolph
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D002540:Cerebral Cortex / Q000473:pathology*; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D006624:Hippocampus / Q000473:pathology*; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000473:pathology; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure*; D009479:Neuropeptides / Q000378:metabolism; D058225:Plaque, Amyloid / Q000473:pathology*; D053764:Presenilin-1 / Q000378:metabolism; D013569:Synapses / Q000648:ultrastructure; D019098:Telomerase / Q000172:deficiency; D016615:Telomere / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure
chemical_list: C545487:APP protein, human; C491049:Aif1 protein, mouse; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002135:Calcium-Binding Proteins; D000089622:Doublecortin Domain Proteins; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D053764:Presenilin-1; D019098:Telomerase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D001973:Bromodeoxyuridine