Cell proliferation and neurogenesis alterations in Alzheimer’s disease and diabetes mellitus mixed murine models

• Published in: Journal of neurochemistry Vol. 154; no. 6; pp. 673 - 692
• Main Authors: Hierro‐Bujalance, Carmen, Marco, Angel, José Ramos‐Rodríguez, Juan, Infante‐Garcia, Carmen, Bella Gomez‐Santos, Sara, Herrera, Marta, Garcia‐Alloza, Monica
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-09-2020
• Subjects: 5’‐bromo‐2’‐desoxy‐uridine; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Animal models; Animals; Body weight; Bromodeoxyuridine - pharmacology; Calcium; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; CD8; CD8 antigen; CD8 Antigens - genetics; CD8 Antigens - metabolism; Cell growth; Cell Proliferation; Complications; Diabetes mellitus; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - pathology; Diet; Diet, High-Fat; doublecortin; Doublecortin protein; Female; Glucose; Glucose tolerance; High fat diet; Iba1; Immunohistochemistry; Immunological tolerance; Insulin; Lymphocytes; Lymphocytes T; Male; Mathematical models; Metabolic disorders; Mice; Mice, Transgenic; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Microglia; Microtubule-Associated Proteins - metabolism; Neurodegenerative diseases; Neurogenesis; Neuropeptides - metabolism; Oligopeptides - genetics; Parameter identification; Peptide Fragments - metabolism; Presenilin 1; Senile plaques; Statistical analysis; Streptozocin; type 1 diabetes; type 2 diabetes; type 1 diabetes; doublecortin; type 2 diabetes; 5’-bromo-2’-desoxy-uridine; CD8; Iba1; Alzheimer's disease
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.14987

The classic neuropathological features of Alzheimer's disease (AD) are accompanied by other complications, including alterations in adult cell proliferation and neurogenesis. Moreover recent studies have shown that traditional markers of the neurogenic process, such as doublecortin (DCX), may also be expressed in CD8+ T cells and ionized calcium‐binding adaptor molecule 1 (Iba1+) microglia, in the close proximity to senile plaques, increasing the complexity of the condition. Altered glucose tolerance, observed in metabolic alteratioins, may accelerate the neurodegenerative process and interfere with normal adult cell proliferation and neurogenesis. To further explore the role of metabolic disease in AD, we analyzed cell proliferation and neurogenesis using 5’‐bromo‐2’‐deoxyuridine and DCX immunohistochemistry in three different mouse models of AD and metabolic alterations: APP/PS1xdb/db mice, APP/PS1 mice on a long‐term high‐fat diet, and APP/PS1 mice treated with streptozotozin. As reported previously, an overall reduction in cell proliferation and neurogenesis was observed after streptozotocin administration. In contrast, an increase in cell proliferation and neurogenesis was detected in neurogenic niches in 14‐ and 26‐week‐old APP/PS1xdb/db mice, accompanied by a slight increase in cortical cell proliferation. While a similar trend was observed in animals on a high‐fat diet, differences were not statistically significant. We observed very few DCX+/CD8+ cells and no DCX+/Iba1+ cells were observed in the close proximity to senile plaques in any of the groups. Interestingly, metabolic parameters such as body weight and glucose and insulin levels were identified as reliable predictors of cell proliferation and neurogenesis in APP/PS1xdb/db mice. Furthermore, metabolic parameters were also associated with altered Aβ levels in the cortex and hippocampus of APP/PS1xdb/db mice. Altogether, our data suggest that metabolic disease may also interfere with central complications in AD.
To study the role of metabolic alterations in Alzheimer´s disease, we analyzed cell proliferation and neurogenesis using 5’‐bromo‐2’‐deoxyuridine and doublecortin immunohistochemistry in three different mouse models of AD and metabolic alterations: APP/PS1xdb/db mice, APP/PS1 mice on long‐term high‐fat diet, and APP/PS1 mice treated with streptozotocin. Cell proliferation and neurogenesis were reduced after streptozotocin administration, while an increase in cell proliferation and neurogenesis was detected in neurogenic niches from APP/PS1xdb/db mice at 14 and 26 weeks of age. Interestingly, metabolic parameters body weight, glucose, and insulin are reliable predictors for cell proliferation and neurogenesis in APP/PS1xdb/db mice.