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

Abstract

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.

Phorbol Diesters and 12-Deoxy-16-hydroxyphorbol 13,16-Diesters Induce TGFα Release and Adult Mouse Neurogenesis

“…Brain damage caused by neurological and vascular disorders or by traumatic injuries is tightly associated with an irreversible neuronal loss, which may lead to cognitive impairment, motor dysfunction, and even alterations of the personality. − Despite the physiological capacity of the adult brain to generate new neurons from neural stem cells (NSC) in the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus, neuronal replacement in damaged brain regions rarely occurs, complicating functional recovery. An association of alterations in neurogenesis with cognitive impairment has been described in mouse models of different metabolic and neurological disorders, , and it is generally accepted that increased neurogenesis leads to improve cognitive performance . Thus, this field demands the discovery of new drugs that regenerate damaged brain regions, facilitating functional recovery.…”

“…The phorbol-containing fraction (Fr4) was purified by open-column chromatography using hexane/EtOAc (30:70−0:100, v/v) to obtain four subfractions which were analyzed by UHPLC−HRMS, taking into account the results of mass spectroscopy of our synthetic phorbol 12,13-diesters. A compound isomeric to phorbol 12-phenylacetate-13isobutyrate (7) was detected in subfraction FR4-4 (58.1 mg), which was further chromatographed through analytic HPLC using Si-60 column and EtOAc/hexane (40% of EtOAc) as the solvent system. Finally, two compounds not described previously, 12-deoxy-16hydroxyphorbol 13-phenylacetate-16-isobutyrate (DPPI, 10, 1.0 mg, 0.0005%, 46.18 min) and 12-deoxy-16-hydroxyphorbol 13-phenylacetate-16-tigliate (DPPT, 11, 1.4 mg, 0.0007%, 51.1 min), were isolated.…”

Poor Cognitive Agility Conservation in Obese Aging People

“…Furthermore, previous studies conducted in mouse models showed that worse metabolic conditions correlate with lower rates of central cell proliferation, increased neurogenesis rates, and progress in cognitive impairment [65,66]. It has been observed that during youth, the body system tries to compensate the generation of new neurons in young mice, but this ability is diminished in adults and the elderly, especially in the presence of a dementia such as AD [67]. Human studies have shown a similar trend and suggest that obesity and AD share the same neurodegenerative mechanisms, promoting in turn, an acceleration of the degenerative process at the central level [68].…”

Physiological Mechanisms Inherent to Diabetes Involved in the Development of Dementia: Alzheimer’s Disease

“…In animal models, it has been shown that an imbalance in insulin levels also impairs neurogenesis in early life [ 107 ], as well as in more mature and long-lived phases [ 37 ]. In addition, the coexistence of T2D with AD pathology reduces neurogenesis and thus neuronal replacement from stages prior to cognitive decline [ 126 ]. Insulin is also involved in the regulation of neuronal and synaptic functions in the hippocampus, cortex and cerebellum, protecting neurons from neurodegeneration and cell death [ 127 , 128 , 129 , 130 ].…”