Dynamics of endogenous Hsp70 synthesis in the brain of olfactory bulbectomized mice

Abstract

Numerous epidemiological studies have established acute brain injury as one of the major risk factors for the Alzheimer's disease (AD). However, the lack of animal models of AD-like degeneration triggered by a defined injury hampered the development of adequate therapies. Here we report that the surgical damage of the olfactory bulbs triggers the development of several pathologies, including amyloid-β accumulation and strong decrease of neuron density in the cortex and hippocampus as well as significant disturbance of spatial memory. Characteristically, these harmful consequences of the olfactory bulbectomy (OBX) have a peculiar dynamics in time with maximal manifestation in periods of 1-1.5 months and 8 months after the surgery and, hence, exhibit biphasic pattern with almost complete recovery period taking place at 5-6 months after the operation. The quantitative determination of endogenous inducible form of Hsp70 in different brain areas of OBX mice demonstrated characteristic fluctuations of Hsp70 levels depending on the time after the operation and age of mice. Interestingly, maximal induction of Hsp70 synthesis in the hippocampus exhibits clear-cut coincidence with the recovery period in OBX animals. The observed correlation enables to suggest curing effect of Hsp70 synthesis at an earlier period of pathology development and establishes it as a possible therapeutic agent for secondary grave consequences of brain injury, such as AD-like degeneration, for which neuroprotective therapy is urgently needed.

Mitochondrial dysfunction in neocortex and hippocampus of olfactory bulbectomized mice, a model of Alzheimer’s disease

“…In both cases, deterioration of olfaction is observed before manifestation of typical clinical symptoms and, there fore, can be used as an early disease marker [32]. The removal of olfactory bulbs in adult rodents (olfactory bulb ectomy, OBX) induces a cascade of neurodegenerative processes similar to those observed in AD, including loss of spatial memory, death of neurons in brain structures responsible for learning and memory, and increased APP synthesis with subsequent formation and accumulation of Aβ [33,34].…”

Localization and Differentiation Pattern of Transplanted Human Multipotent Mesenchymal Stromal Cells in the Brain of Bulbectomized Mice

“…At the age of 2 months, the mice were subjected to OBE; this procedure induced the development of Alzheimer-type neurodegeneration that was most pronounced in 8 months after surgery [1,6]. OBE was performed under sterile conditions under Nembutal narcosis (40 mg/kg, intraperitoneally); 0.5% Novocain was used for local anesthesia during scalping.…”

“…Age-matched controls were subjected to sham operation without olfactory bulb aspiration [1,6]. Completeness of olfactory bulb removal was verifi ed during subsequent morphological examination of the brain.…”

“…These aspects can be studied on animal models of the corresponding diseases. Olfactory bulbectomy (OBE) is a model of sporadic AD characterized by accumulation of β-amyloid oligomers in the brain tissue, cell death in AD-affected areas, and learning and memory disturbances [1,6]. We have previously demonstrated that systemic transplantation of MMSC prevents spatial memory impairment in OBE animals [2].…”

The importance of the cellular stress response in the pathogenesis and treatment of type 2 diabetes

“…While iHSPs have not been measured in neurons or beta cells in vivo, loss of insulin signaling likely reduces iHSPs in these tissues, resulting in abnormal protein accumulation and function. Administering insulin and Hsp70 can reduce amyloid accumulation in the brain (Tang et al 2013;Huang et al 2014;Bobkova et al 2013).…”