title: Aging without Apolipoprotein D: Molecular and cellular modifications in the hippocampus and cortex.
abstract: A detailed knowledge of the mechanisms underlying brain aging is fundamental to understand its functional decline and the baseline upon which brain pathologies superimpose. Endogenous protective mechanisms must contribute to the adaptability and plasticity still present in the healthy aged brain. Apolipoprotein D (ApoD) is one of the few genes with a consistent and evolutionarily conserved up-regulation in the aged brain. ApoD protecting roles upon stress or injury are well known, but a study of the effects of ApoD expression in the normal aging process is still missing. Using an ApoD-knockout mouse we analyze the effects of ApoD on factors contributing to the functional maintenance of the aged brain. We focused our cellular and molecular analyses in the cortex and hippocampus at an age representing the onset of senescence where mortality risks are below 25%, avoiding bias towards long-lived animals. Lack of ApoD causes a prematurely aged brain without altering lifespan. Age-dependent hyperkinesia and memory deficits are accompanied by differential molecular effects in the cortex and hippocampus. Transcriptome analyses reveal distinct effects of ApoD loss on the molecular age-dependent patterns of the cortex and hippocampus, with different cell-type contributions to age-regulated gene expression. Markers of glial reactivity, proteostasis, and oxidative and inflammatory damage reveal early signs of aging and enhanced brain deterioration in the ApoD-knockout brain. The lack of ApoD results in an age-enhanced significant reduction in neuronal calcium-dependent functionality markers and signs of early reduction of neuronal numbers in the cortex, thus impinging upon parameters clearly differentiating neurodegenerative conditions from healthy brain aging. Our data support the hypothesis that the physiological increased brain expression of ApoD represents a homeostatic anti-aging mechanism.
authors: Instituto de Biología y Genética Molecular-Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid-CSIC, Valladolid, Spain.
authors: Diego
authors: D
authors: Sanchez
authors: Instituto de Biología y Genética Molecular-Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid-CSIC, Valladolid, Spain.
authors: Raquel
authors: R
authors: Bajo-Grañeras
authors: Instituto de Biología y Genética Molecular-Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid-CSIC, Valladolid, Spain.
authors: Manuela
authors: M
authors: Del Caño-Espinel
authors: Instituto de Biología y Genética Molecular-Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid-CSIC, Valladolid, Spain.
authors: Rosa
authors: R
authors: Garcia-Centeno
authors: Instituto de Biología y Genética Molecular-Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid-CSIC, Valladolid, Spain.
authors: Nadia
authors: N
authors: Garcia-Mateo
authors: Instituto de Biología y Genética Molecular-Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid-CSIC, Valladolid, Spain.
authors: Raquel
authors: R
authors: Pascua-Maestro
authors: Instituto de Biología y Genética Molecular-Departamento de Bioquímica y Biología Molecular y Fisiología, Universidad de Valladolid-CSIC, Valladolid, Spain. Electronic address: opabinia@ibgm.uva.es.
authors: Maria D
authors: MD
authors: Ganfornina
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019588:Aging, Premature / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D053399:Apolipoproteins D / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D059467:Transcriptome
chemical_list: D053399:Apolipoproteins D
keywords: Cognitive decline; Immune response; Lipocalin; Neurodegeneration; Oxidative stress; Reactive gliosis