Alterations in local thyroid hormone signaling in the hippocampus of the SAMP8 mouse at younger ages: Association with delayed myelination and behavioral abnormalities

Abstract

The senescence-accelerated mouse (SAM) strains were established through selective inbreeding of the AKR/J strain based on phenotypic variations of aging and consist of senescence-prone (SAMP) and senescence-resistant (SAMR) strains. Among them, SAMP8 is considered as a model of neurodegeneration displaying age-associated learning and memory impairment and altered emotional status. Because adult hypothyroidism is one of the common causes of cognitive impairment and various psychiatric disorders, we examined the possible involvement of thyroid hormone (TH) signaling in the pathological aging of SAMP8 using the senescence-resistant SAMR1 as control. Although plasma TH levels were similar in both strains, a significant decrease in type 2 deiodinase (D2) gene expression was observed in the SAMP8 hippocampus from 1 to 8 months of age, which led to a 35–50% reductions at the protein level and 20% reduction of its enzyme activity at 1, 3, and 5 months. D2 is responsible for local conversion of thyroxine into transcriptionally active 3,5,3′-triiodothyronine (T3), so the results suggest a reduction in T3 level in the SAMP8 hippocampus. Attenuation of local TH signaling was confirmed by downregulation of TH-dependent genes and by immunohistochemical demonstration of delayed and reduced accumulation of myelin basic protein, the expression of which is highly dependent on TH. Furthermore, we found that hyperactivity and reduced anxiety were not age-associated but were characteristic of young SAMP8 before they start showing impairments in learning and memory. Early alterations in local TH signaling may thus underlie behavioral abnormalities as well as the pathological aging of SAMP8. © 2012 Wiley Periodicals, Inc.

Proinsulin protects against age-related cognitive loss through anti-inflammatory convergent pathways

“…SAMP8 mice showed reactive astrocytes in the hippocampus. Previous authors have demonstrated that the number of astrocytic cell bodies remained constant with age in the SAMP8 hippocampus despite increased GFAP immunoreactivity, thus indicating a change in hypertrophic reactivity (Sawano et al, 2013). SAMP8 reactive astrocytes appear to play a significant role in exaggerated and long-lasting brain inflammatory responses against stress factors and subsequent impairment of memory in SAMP8.…”

“…Motor activity and ambulation was tested in both mouse strains to discard any local effect of the vector injection. Furthermore, SAMP8 mice are reported to display non-cognitive alterations, such as sensorimotor impairment, hyperactivity, and reduced anxiety-like behavior compared with SAMR1 (Markowska et al, 1998;Miyamoto et al, 1992;Sawano et al, 2013). These non-cognitive behaviors were also tested for proinsulin-induced changes.…”

Nodes and biological processes identified on the basis of network analysis in the brain of the senescence accelerated mice as an Alzheimer's disease animal model

“…Using SAM/resistant-1 (SAMR1) as a control, the senescence accelerated mouse prone-8 (SAMP8) is a robust model of AD because it shares phenotypes that resemble the symptoms of late-onset and age-related sporadic AD patients and because has distinct advantages over the gene-modified model (Pang et al, 2006; Pallas et al, 2008; Woodruff-Pak, 2008; Tomobe and Nomura, 2009; Morley et al, 2012; Pallàs, 2012). Although investigators have developed new therapies and have tested in detail, the structural (Gutierrez-Cuesta et al, 2007; del Valle et al, 2012; Li et al, 2012), functional (Sureda et al, 2006; Tajes et al, 2008; Lou et al, 2012; Yamaguchi et al, 2012) and behavioral consequences (Gong et al, 2008; Shi et al, 2010b; Shih et al, 2010; Chang et al, 2012; Kanno et al, 2012; Lopez-Ramos et al, 2012; Lou et al, 2012; Orejana et al, 2012; Dobarro et al, 2013; Huang et al, 2013; Sawano et al, 2013) of AD-associated pathology based on SAMP8 mice, little progress has been made with regard to the patho-physiological mechanisms of SAMP8 mice, and the underlying causes of the AD-like phenotype in SAMP8 mice remain unknown.…”

Reduction in NPY‐positive neurons and dysregulation of excitability in young senescence‐accelerated mouse prone 8 (SAMP8) hippocampus precede the onset of cognitive impairment

“…In spite of normal serum TH levels, TH signaling in the SAMP8 hippocampus was thus significantly attenuated as monitored by the reduction in the expression of typical TH‐dependent genes (Sawano et al . ).…”