Impairments of Synaptic Plasticity in Aged Animals and in Animal Models of Alzheimer's Disease

Balietti, Marta; Tamagnini, Francesco; Fattoretti, Patrizia; Burattini, Costanza; Casoli, Tiziana; Platano, Daniela; Lattanzio, Fabrizia; Aicardi, Giorgio

doi:10.1089/rej.2012.1318

Cited by 34 publications

(20 citation statements)

References 29 publications

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“…, MAPK and Wnt signaling) and neuronal plasticity ( e.g. , long-term potentiation), and dysfunction of these processes are known to contribute to both T2D and AD (Balietti et al, 2012; Bordonaro, 2009; Cruz et al, 2013; Evans et al, 2002; Kim and Choi, 2010; Lee et al, 2010; Rios et al, 2014; Wang et al, 2013). …”

Section: Resultsmentioning

confidence: 99%

Shared genetic etiology underlying Alzheimer's disease and type 2 diabetes

Hao

Narzo

et al. 2015

Molecular Aspects of Medicine

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Epidemiological evidence supports the observation that subjects with type 2 diabetes (T2D) are at higher risk to develop Alzheimer’s disease (AD). However, whether and how these two conditions are causally linked is unknown. Possible mechanisms include shared genetic risk factors, which were investigated in this study based on recent genome wide association study (GWAS) findings. In order to achieve our goal, we retrieved single nucleotide polymorphisms (SNPs) associated with T2D and AD from large-scale GWAS meta-analysis consortia and tested for overlap among the T2D- and AD-associated SNPs at various p-value thresholds. We then explored the function of the shared T2D/AD GWAS SNPs by leveraging expressional quantitative trait loci, pathways, gene ontology data, and co-expression networks. We found 927 SNPs associated with both AD and T2D with p-value ≤0.01, an overlap significantly larger than random chance (overlapping p-value of 6.93E−28). Among these, 395 of the shared GWAS SNPs have the same risk allele for AD and T2D, suggesting common pathogenic mechanisms underlying the development of both AD and T2D. Genes influenced by shared T2D/AD SNPs with the same risk allele were first identified using a SNP annotation variation (ANNOVAR) software, followed by using Association Protein-Protein Link Evaluator (DAPPLE) software to identify additional proteins that are known to physically interact with the ANNOVAR gene annotations. We found that gene annotations from ANNOVAR and DAPPLE significantly enriched specific KEGG pathways pertaining to immune responses, cell signaling and neuronal plasticity, cellular processes in which abnormalities are known to contribute to both T2D and AD pathogenesis. Thus, our observation suggests that among T2D subjects with common genetic predispositions (e.g., SNPs with consistent risk alleles for T2D and AD), dysregulation of these pathogenic pathways could contribute to the elevated risks for AD in subjects. Interestingly, we found that 532 of the shared T2D/AD GWAS SNPs had divergent risk alleles in the two diseases. For individual shared T2D/AD SNPs with divergent alleles, one of the allelic forms may contribute to one of the diseases (e.g., T2D), but not necessarily to the other (e.g., AD), or vice versa. Collectively, our GWAS studies tentatively support the epidemiological observation of disease concordance between T2D and AD. Moreover, the studies provide the much needed information for the design of future novel therapeutic approaches, for a subpopulation of T2D subjects with genetic disposition to AD, that could benefit T2D and reduce the risk for subsequent development of AD.

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Section: Resultsmentioning

confidence: 99%

Shared genetic etiology underlying Alzheimer's disease and type 2 diabetes

Hao

Narzo

et al. 2015

Molecular Aspects of Medicine

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“…Age-related changes in the levels of neurotrophic factors have also been shown in middle-aged rodents (Bimonte-Nelson et al, 2008;Hattiangady et al, 2005;Shetty et al, 2005). Decreased plasticity in middle-aged and aged rodents (Kumar, 2011;Rex et al, 2005) may also play a role in cognitive impairment (Balietti et al, 2012). In this context, it is interesting that antidepressants, which have been shown to have pro-cognitive effects in some animal models (Elizalde et al, 2008;Schilstrom et al, 2011), also alter stem cell proliferation (Ibi et al, 2008), growth factor expression (Song et al, 2006) and neuroplasticity-related gene expression (Djordjevic et al, 2012;Freitas et al, 2013), which could underlie the effects of antidepressants on cognitive function as well as mood.…”

Section: Introductionmentioning

confidence: 95%

Reversal of age-associated cognitive deficits is accompanied by increased plasticity-related gene expression after chronic antidepressant administration in middle-aged mice

Abdourahman

Tamm

et al. 2015

Pharmacology Biochemistry and Behavior

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Cognitive decline occurs during healthy aging, even in middle-aged subjects, via mechanisms that could include reduced stem cell proliferation, changed growth factor expression and/or reduced expression of synaptic plasticity genes. Although antidepressants alter these mechanisms in young rodents, their effects in older animals are unclear. In middle-aged mice, we examined the effects of a selective serotonin reuptake inhibitor (fluoxetine) and a multimodal antidepressant (vortioxetine) on cognitive and affective behaviors, brain stem cell proliferation, growth factor and gene expression. Twelve-month-old female C57BL/6 mice exhibited impaired visuospatial memory in the novel object placement (location) task associated with reduced expression of several plasticity-related genes. Chronic treatment with vortioxetine, but not fluoxetine, improved visuospatial memory and reduced depression-like behavior in the forced swim test in middle-aged mice. Vortioxetine, but not fluoxetine, increased hippocampal expression of several neuroplasticity-related genes in middle-aged mice (e.g., Nfkb1, Fos, Fmr1, Camk2a, Arc, Shank1, Nlgn2, and Rab3a). Neither drug reversed the age-associated decrease in stem cell proliferation. Hippocampal growth factor levels were not consistent with behavioral outcomes. Thus, a change in the expression of multiple genes involved in neuronal plasticity by antidepressant treatment was associated with improved cognitive function and a reduction in depression-like behavior in middle-aged mice.

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“…29,30 Disruption of AMPAR trafficking by soluble amyloid b (Ab) oligomers is a major factor in synaptic dysfunction in Alzheimer disease. 31,32 The effect is partly due to competition with proteolytic maturation of BDNF, which is required for its effect on synaptic potentiation. 33 Thus, therapeutic intervention in AMPA trafficking during aging may also reduce soluble Ab oligomer-induced synaptic dysfunctions.…”

Section: Medical Implicationsmentioning

confidence: 99%

Age-Related Impairment of Visual Recognition Memory Correlates with Impaired Synaptic Distribution of GluA2 and Protein Kinase Mζ in the Dentate Gyrus

Aicardi

2012

Rejuvenation Research

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Age-related functional alterations in the perforant path projection from the entorhinal cortex to the dentate gyrus (DG) of the hippocampus play a major role in age-related memory impairments, but little is known about the molecular mechanisms responsible for these changes. In a recent study, young and aged monkeys were tested on the visual recognition memory test "delayed nonmatching-to-sample"; then, electron microscopic immunocytochemistry was performed in the hippocampal DG to determine the subcellular localization of the GluA2 subunit of the glutamate α-amino-3-hydroxy-5-methyl-4- isoxazole-propionic acid receptor (AMPAR) and protein kinase Mζ (PKMζ), which promotes memory storage by regulating GluA2-containing AMPAR trafficking. The results obtained suggest that age-related deficits in visual recognition memory are coupled with impairment in PKMζ-dependent maintenance of GluA2 at the synapse. Together with previous evidences of the critical role of PKMζ in memory consolidation, these data render this enzyme an attractive potential therapeutic target for treating age-related memory decline, and support the view that the pharmacological manipulation of AMPAR trafficking in the synapses may provide new insights in the search of memory enhancers for aged individuals, including those affected by Alzheimer disease.

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Impairments of Synaptic Plasticity in Aged Animals and in Animal Models of Alzheimer's Disease

Cited by 34 publications

References 29 publications

Shared genetic etiology underlying Alzheimer's disease and type 2 diabetes

Shared genetic etiology underlying Alzheimer's disease and type 2 diabetes

Reversal of age-associated cognitive deficits is accompanied by increased plasticity-related gene expression after chronic antidepressant administration in middle-aged mice

Age-Related Impairment of Visual Recognition Memory Correlates with Impaired Synaptic Distribution of GluA2 and Protein Kinase Mζ in the Dentate Gyrus

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