ABSTRACT
No model fully recapitulates the neuropathology of Alzheimer's disease (AD). Although the triple-transgenic mouse model of AD (3xTg-AD) expresses Aß plaques and tau-laden neurofibrillary tangles, as well as synaptic and behavioral deficits, it does not display frank neuronal loss. Because old age is the most important risk factor in AD, senescence-related interactions might be lacking to truly establish an AD-like environment. To investigate this hypothesis, we bred the 3xTg-AD mouse with the senescence-accelerated mouse prone 8 (SAMP8), a model of accelerated aging. We generated four groups of heterozygous mice with either the SAMP8 or SAMR1 (senescence-resistant-1) genotype, along with either the 3xTg-AD or non-transgenic (NonTg) genotype. Despite no differences among groups in total latency to escape the Barnes maze, a greater number of errors were noticed before entering the target hole in 19-month-old P8/3xTg-AD mice at day 5, compared to other groups. Postmortem analyses revealed increased cortical levels of phospho-tau (Thr231) in female P8/3xTg-AD mice (+277% vs. R1/3xTg-AD mice), without other tau-related changes. Female P8/3xTg-AD mice exhibited higher cortical soluble Aß40 and Aß42 concentrations (Aß40, +85%; Aß42, +35% vs. R1/3xTg-AD), whereas insoluble forms remained unchanged. Higher Aß42 load coincided with increased astroglial activation in female P8/3xTg-AD mice, as measured with glial fibrillary acidic protein (GFAP) (+57% vs. R1/3xTg-AD mice). To probe neuronal degeneration, concentrations of neuronal nuclei (NeuN) were measured, but no differences were detected between groups. Altogether, the SAMP8 genotype had deleterious effects on spatial memory and exerted female-specific aggravation of AD neuropathology without overt neurodegeneration in 3xTg-AD mice.
Subject(s)
Alzheimer Disease , Disease Models, Animal , Mice, Transgenic , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/psychology , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Anxiety/metabolism , Anxiety/pathology , Apolipoproteins E/metabolism , Body Weight/physiology , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Female , Glial Fibrillary Acidic Protein/metabolism , Gliosis/metabolism , Gliosis/pathology , Humans , Mice, 129 Strain , Mice, Inbred C57BL , Motor Activity/physiology , Peptide Fragments/metabolism , Spatial Memory/physiology , Species Specificity , tau Proteins/genetics , tau Proteins/metabolismABSTRACT
Stem cell-based therapy has been proposed as a potential means of treatment for a variety of brain disorders. Because ethical and technical issues have so far limited the clinical translation of research using embryonic/fetal cells and neural tissue, respectively, the search for alternative sources of therapeutic stem cells remains ongoing. Here, we report that upon transplantation into mice with chemically induced hippocampal lesions, human olfactory ecto-mesenchymal stem cells (OE-MSCs) - adult stem cells from human nasal olfactory lamina propria - migrated toward the sites of neural damage, where they differentiated into neurons. Additionally, transplanted OE-MSCs stimulated endogenous neurogenesis, restored synaptic transmission, and enhanced long-term potentiation. Mice that received transplanted OE-MSCs exhibited restoration of learning and memory on behavioral tests compared with lesioned, nontransplanted control mice. Similar results were obtained when OE-MSCs were injected into the cerebrospinal fluid. These data show that OE-MSCs can induce neurogenesis and contribute to restoration of hippocampal neuronal networks via trophic actions. They provide evidence that human olfactory tissue is a conceivable source of nervous system replacement cells. This stem cell subtype may be useful for a broad range of stem cell-related studies.
