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P‐133: GRK5 deficient mouse is a novel model for early Alzheimer's disease
Author(s) -
Suo Zhiming,
Bartelli Nicholas,
Rasul Imtiaz,
Wu Guisheng,
Li Longxuan,
Premont Richard T.,
Arendash Gary W.
Publication year - 2007
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2007.04.197
Subject(s) - presenilin , neurodegeneration , pathogenesis , biology , alzheimer's disease , tau protein , neuroscience , genetically modified mouse , hippocampus , amyloid (mycology) , pathology , disease , transgene , medicine , immunology , genetics , botany , gene
This work suggests for the first time that there is a connection between the weakening of the immune system and memory deficits that accompany the natural process of aging. Background: We have demonstrated that peripheral immunity contributes to adult hippocampal neurogenesis and spatial learning/memory abilities, and that this is mediated in part by T lymphocytes recognizing brain antigens such as myelin proteins. The potency of the immune system dramatically decreases in aged individuals; with the most prominent feature of age-related immune senescence being thymic involution, resulting in a reduced naı̈ve T cell repertoire. Also the incidence of cellular autoimmune diseases reduces with age. According to the above, we hypothesized that age-related decrease in neurogenesis as well as the age-related loss of certain cognitive activities can be partially explained by the aging immune system. Objective: To investigate how T cells contribute to brain plasticity, and how this changes with age. Are T cells needed continuously throughout life, and are they important for learning or memory, or both? Methods: We compared wild-type and immune-deficient mice, at different ages, with respect to hippocampal neurogenesis and functional performance in two hippocampal-dependent memory tasks. We also generated chimeras by transplanting young adult C57Bl/6J wild-type mice with bone marrow taken from immune deficient mice, and examined their hippocampal neurogenesis and their spatial learning/memory capabilities. Results: In immune deficient mice, impaired neurogenesis and learning/memory abilities were evident at 4 weeks of age. Interestingly, the difference between wild-type and immune-deficient mice in terms of progenitor-cell proliferation in the hippocampus was relatively small at infancy, increasing at adulthood and decreasing again in old age. Discriminating learning from memory in the MWM revealed that immune deficient mice suffer from hippocampal-dependent spatial memory deficits. Similar results were obtained with the chimeras. Memory deficits correlated with a decrease in BDNF expression in the hippocampus. Conclusions: T cells are needed continuously for hippocampal neural cell renewal and the establishment of new hippocampal-dependent memories. Based on the above results, it is possible that immune-based manipulations (for example, T cell-based vaccination) could restore or even prevent age-related loss of neurogenesis and memory.