Impaired Learning and Memory Ability Induced by a Bilaterally Hippocampal Injection of Streptozotocin in Mice: Involved With the Adaptive Changes of Synaptic Plasticity

Abstract

Background: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, psychiatric symptoms and behavioral disorders, resulting in disability, and loss of self-sufficiency.Objective: To establish an AD-like mice model, investigate the behavioral performance, and explore the potential mechanism.Methods: Streptozotocin (STZ, 3 mg/kg) was microinjected bilaterally into the dorsal hippocampus of C57BL/6 mice, and the behavioral performance was observed. The serum concentrations of insulin and nesfatin-1 were measured by ELISA, and the activation of hippocampal microglia and astrocytes was assessed by immunohistochemistry. The protein expression of several molecular associated with the regulation of synaptic plasticity in the hippocampus and the pre-frontal cortex (PFC) was detected via western blotting.Results: The STZ-microinjected model mice showed a slower bodyweight gain and higher serum concentration of insulin and nesfatin-1. Although there was no significant difference between groups with regard to the ability of balance and motor coordination, the model mice presented a decline of spontaneous movement and exploratory behavior, together with an impairment of learning and memory ability. Increased activated microglia was aggregated in the hippocampal dentate gyrus of model mice, together with an increase abundance of Aβ1−42 and Tau in the hippocampus and PFC. Moreover, the protein expression of NMDAR2A, NMDAR2B, SynGAP, PSD95, BDNF, and p-β-catenin/β-catenin were remarkably decreased in the hippocampus and the PFC of model mice, and the expression of p-GSK-3β (ser9)/GSK-3β were reduced in the hippocampus.Conclusion: A bilateral hippocampal microinjection of STZ could induce not only AD-like behavioral performance in mice, but also adaptive changes of synaptic plasticity against neuroinflammatory and endocrinal injuries. The underlying mechanisms might be associated with the imbalanced expression of the key proteins of Wnt signaling pathway in the hippocampus and the PFC.

Tau Cleavage Contributes to Cognitive Dysfunction in Strepto-Zotocin-Induced Sporadic Alzheimer’s Disease (sAD) Mouse Model

“…In this context, intracerebroventricular (ICV) infusion(s) of streptozotocin (STZ), a diabetogenic compound inducing in a laboratory animal a systemic resistance to insulin, can mimic some pathological aspects observed in brain of sAD subjects. Indeed, adult rodents that underwent STZ infusion develop cerebral accumulation of Aβ [11], increased tau phosphorylation and aggregation [12,13], oxidative stress as revealed by increased levels of malondialdehyde and decreased levels of glutathione [14][15][16], changes in insulin signaling [17], dysmetabolism of glucose and energy production [18][19][20], down-regulation of ChAT activity [21], gliosis [12,22,23], caspase(s) activation and apoptosis [24], alteration in synaptic proteins and long-term cognitive deficits [20,[25][26][27][28]. The insulin/phosphoinositide 3-kinase/protein kinase B/glycogen synthase kinase-3β (insulin/PI3K/AKT/GSK3-β) pathway, which regulates glucose metabolism in the brain [20,29,30], is down-regulated in ICV-infused STZ mice along with inactivation of AMP-activated protein kinase (AMPK) signaling cascade, a kinase acting as master sensor of energy balance in mammalian cells [31].…”

Exosomes derived from bone-marrow mesenchymal stem cells alleviate cognitive decline in AD-like mice by improving BDNF-related neuropathology

“…It has been reported that lateral ventricle injection of STZ could induce AD-like behavior in rats [ 32 ] or mice [ 33 – 37 ], as indicated by significant cognitive impairment and increased Aβ 1-42 accumulation and hyperphosphorylated tau in the hippocampus [ 32 ], along with increased glial activation or decreased expression of synapse-associated protein [ 33 – 37 ]. In our previous study, STZ was administered via bilateral hippocampal injection, and the mice displayed impaired learning and memory abilities, together with insulin resistance and hyperactivated microglial and alternative synaptic plasticity in the hippocampus [ 38 ]. Consistently, in the present study, our results showed that lateral ventricle injection of STZ mice could induce AD-like behavioral performance in mice, as indicated by the decreased frequency, duration, and distance traveled in the center area and reduced rearing frequency in the OFT, increased immobility in the TST, and the decreased preference index of novel object or arm in the NOR or Y-maze.…”

“…Synaptic plasticity is a crucial basis for regulating learning and memory functions [ 38 ]. It has long been demonstrated that the expression levels of synapse-related proteins such as Syt-1 and synapsin-1 are significantly reduced in the hippocampal tissues of postmortem AD patients and animal models [ 33 , 37 , 55 , 56 ].…”

“…The brains were dissected immediately, and hippocampal tissues were isolated and stored in liquid nitrogen. The Western blot method was performed as described in our previous research [ 30 ], using RIPA (P0013B, Beyotime) lysate containing protease inhibitors and phosphatase inhibitors to lyse the tissues and using the BCA protein quantification kit (P0010, Beyotime) to determine the protein concentration in each sample. The protein loading buffer and protein sample were mixed in boiling water and heated for 10 min.…”

Protective Effect of Exosomes Derived from Bone Marrow Mesenchymal Stem Cells Against AD-Like Behaviors in Mice: Involvement with Regulating Glial Activation and its Associated Neuroinflammation and BDNF-Related Neuropathological Changes in the Hippocampus

“…Synaptic plasticity is the material basis for regulating learning and memory functions [55]. It has been long demonstrated that the expression levels of synapse-related proteins such as Synaptotagmin-1 and Synapsin-1 are signi cantly reduced in the hippocampal tissues of postmortem AD patients and animal…”