Intra-Hippocampal Transplantation of Neural Precursor Cells with Transgenic Over-Expression of IL-1 Receptor Antagonist Rescues Memory and Neurogenesis Impairments in an Alzheimer’s Disease Model

Abstract

Ample evidence implicates neuroinflammatory processes in the etiology and progression of Alzheimer's disease (AD). To assess the specific role of the pro-inflammatory cytokine interleukin-1 (IL-1) in AD we examined the effects of intra-hippocampal transplantation of neural precursor cells (NPCs) with transgenic over-expression of IL-1 receptor antagonist (IL-1raTG) on memory functioning and neurogenesis in a murine model of AD (Tg2576 mice). WT NPCs- or sham-transplanted Tg2576 mice, as well as naive Tg2576 and WT mice served as controls. To assess the net effect of IL-1 blockade (not in the context of NPCs transplantation), we also examined the effects of chronic (4 weeks) intra-cerebroventricular (i.c.v.) administration of IL-1ra. We report that 12-month-old Tg2576 mice exhibited increased mRNA expression of hippocampal IL-1β, along with severe disturbances in hippocampal-dependent contextual and spatial memory as well as in neurogenesis. Transplantation of IL-1raTG NPCs 1 month before the neurobehavioral testing completely rescued these disturbances and significantly increased the number of endogenous hippocampal cells expressing the plasticity-related molecule BDNF. Similar, but less-robust effects were also produced by transplantation of WT NPCs and by i.c.v. IL-1ra administration. NPCs transplantation produced alterations in hippocampal plaque formation and microglial status, which were not clearly correlated with the cognitive effects of this procedure. The results indicate that elevated levels of hippocampal IL-1 are causally related to some AD-associated memory disturbances, and provide the first example for the potential use of genetically manipulated NPCs with anti-inflammatory properties in the treatment of AD.

Applications of the Keap1–Nrf2 system for gene and cell therapy

“…In addition, over-expression of the antagonist of the pro-inflammatory cytokine interleukin-1 in neural precursor cells (NPCs) rescues memory impairments in a mouse model of AD. The effect is more robust than that observed when WT NPCs were used for transplantation [190] . Although the protective nature of Nrf2 is unquestionable, surprisingly little effort has been placed on assessing the potential of Nrf2 in stem cell therapy applications.…”

Chronic Progressive Neurodegeneration in a Transgenic Mouse Model of Prion Disease

“…For example, this drawback is seen in most transgenic animal models of familial Alzheimer's disease, which exhibit typical pathologic features, including widespread deposition of β-amyloid plaques but without associated neuronal loss (Oddo et al, 2003a,b; Savonenko et al, 2005; Radde et al, 2006). Furthermore, memory impairment in the double-transgenic animal model of Alzheimer's disease is independent of hippocampal neuronal volume, and is completely reversed by inhibiting innate immune cytokines, namely interleukin-1(Ben-Menachem-Zidon et al, 2014), and TNFα (Tweedie et al, 2012). Even the commonly-used animal model of familial Alzheimer's disease, carrying a cassette of 5 mutated human genes (the 5XFAD mouse) that has been reported to express β-amyloid plaques as early as age 2 months and memory impairment at 4 months, exhibits only limited neuronal loss, observed mainly in cortical layer 5 and subiculum of the hippocampus at 9 months (Oakley et al, 2006).…”

Exercise as a pro-cognitive, pro-neurogenic and anti-inflammatory intervention in transgenic mouse models of Alzheimer’s disease

“…Indeed, several studies have assessed cognitive function simultaneously with hippocampal neurogenesis. Deficits in spatial memory (Ben-Menachem-Zidon et al, 2014;Choi et al, 2014b;Iascone et al, 2013;Tapia-Rojas et al, 2016;Valero et al, 2011), spontaneous alternation (Li et al, 2015), contextual memory (Ben- MenachemZidon et al, 2014;Imbimbo et al, 2010) and recognition memory (Biscaro et al, 2012;Blanchard et al, 2010) have all been observed to occur alongside reductions in hippocampal neurogenesis. Interestingly, Yu et al (2009) report that nine month old APP + PS-1 mice are impaired in the MWM task and have increased hippocampal neurogenesis.…”