Elsevier

Psychoneuroendocrinology

Volume 65, March 2016, Pages 15-25
Psychoneuroendocrinology

Long-term central pathology and cognitive impairment are exacerbated in a mixed model of Alzheimer’s disease and type 2 diabetes

https://doi.org/10.1016/j.psyneuen.2015.12.001Get rights and content

Highlights

  • APP/PS1xdb/db mice show long-term cross-talk between metabolic and central deficits.

  • Brain atrophy in aged APP/PS1xdb/db mice is accompanied by reduced neuronal density.

  • Old APP/PS1xdb/db mice present increased axonal curvature and reduced spine density.

  • Spontaneous central bleeding is synergistically worsened in aged APP/PS1xdb/db mice.

  • Severe cognitive problems are observed in aged APP/PS1xdb/db mice.

Abstract

Type 2 diabetes (T2D) is a well-characterized risk factor for Alzheimer’s disease (AD), the most common cause of dementia. Since both, T2D and dementia are closely related to aging and they chronically coexist in elderly patients, it is of particular relevance to know whether long-term evolution of T2D and dementia interfere with each other years after the onset of the diseases. In order to elucidate this interaction, we have characterized a mixed model of T2D and AD, the APP/PS1xdb/db mouse, at 36 weeks of age, when both diseases have long coexisted and evolved. In aged APP/PS1xdb/db mice we observed dysfunctional metabolic control, when compared with diabetic mice alone, suggesting that AD may also contribute to T2D pathology in the long-term. Learning and memory were severely impaired in APP/PS1xdb/db mice, accompanied by reduced cortical size, neuronal branching simplification and reduction of dendritic spine density. Increased tau phosphorylation was also observed in old APP/PS1xdb/db mice. A shift in amyloid-β (Aβ) pathology was detected, and while insoluble Aβ was reduced, more toxic soluble species were favoured. Microglia burden was significantly increased in the proximity of senile plaques and an overall increase of spontaneous haemorrhages was also observed in APP/PS1xdb/db mice, suggesting a possible disruption of the blood brain barrier in the mixed model. It is therefore feasible that strict metabolic control may slow or delay central complications when T2D and dementia coexist in the long term.

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia. Senile plaques (SP) mainly composed by amyloid-beta (Aβ), neurofibrillary tangles with abnormally phosphorylated tau, and neuronal and synaptic loss are the cardinal neuropathological features of AD (Serrano-Pozo et al., 2011). AD pathologies regularly coexist with vascular injury and other co-morbidities in many patients, making the borderlines between AD and other dementias blurred in many cases (Craft, 2009).

The ultimate causes of dementia are not completely understood. Metabolic disorders including type 2 diabetes (T2D), have been identified as important risk factors for developing sporadic AD (Craft, 2009). In support of this idea, epidemiological and clinical studies have revealed a close relationship between T2D and dementia (Ott et al., 1996, Arvanitakis et al., 2004). Moreover, improved metabolic control can significantly ameliorate cognitive dysfunction (Craft et al., 2003, Plastino et al., 2010, Cooray et al., 2011). Also, at a molecular level some relevant links between T2D and AD support the interaction between these diseases. For example: T2D progression correlates with pancreatic amylin deposition, in a similar way to Aβ deposition in AD brain. Since insulin, amylin and Aβ are all degraded by neprilysin and insulin degrading enzyme, these substrates may compete with each other. Also, an imbalance of any of these substrates, as observed in AD or T2D, can affect the degradation rate of other substrates and possibly influence the pathogenesis of related diseases (Gotz et al., 2009). Aβ oligomers may also interfere with insulin signalling in hippocampal neurons (Zhao et al., 2008). On the other hand insulin may regulate Aβ levels by modulation of β and γ secretases (Farris et al., 2003). Central nervous system insulin receptors are highly expressed in regions relevant for cognition, such as cortex and hippocampus. This is consistent with evidence showing that insulin influences memory (Craft, 2009). Since vascular damage has been suggested to reduce Aβ clearance along interstitial fluid drainage pathways (Weller et al., 2008, Garcia-Alloza et al., 2011), and insulin participates in neurovascular regulation, it is feasible that metabolic alterations may also underlie the crosstalk between T2D and AD (Correia et al., 2011).

While T2D seems to play a relevant role in developing AD, aging remains the main risk factor for both dementia and T2D. Therefore, examining animal models that harbour both AD and T2D during advanced aging, when both pathologies are fully established, might more closely resemble the natural history of T2D and dementia. Therefore, we have analyzed the relationship between T2D and AD in a complex model resulting from crossing an AD mouse model with amyloid pathology (APPswe/PS1dE9, APP/PS1 from now on) with a classical T2D model, the db/db mouse. To our knowledge, the long-term effect of this relationship has not been studied. At 36 weeks of age, both T2D and AD plaque pathology are fully established and have chronically evolved over time, as observed in patients. We detected a synergistic effect between T2D and AD that worsened with aging. Significant cognitive impairment was observed in APP/PS1xdb/db mice, accompanied by reduced cortical size and tau pathology. Moreover, a significant reduction in spine density was observed in APP/PS1xdb/db mice, similar to the synapse loss observed in AD patients. We also detected a shift in Aβ pathology. Insoluble Aβ levels and SP were reduced, while more toxic soluble species were favoured. Inflammation was highly elevated in APP/PS1xdb/db mice and spontaneous bleeding was worsened in the cortex and hippocampus from our mixed animal model. It is possible that inflammatory process resulting from T2D and AD, and blood brain barrier alterations, might underlie pathological and cognitive features observed in APP/PS1xdb/db mice in the long term.

Section snippets

Animals

APP/PS1xdbdb mice were produced by cross-breeding an AD model:APPswe/PS1dE9 mice (APP/PS1) (Jankowsky et al., 2004) (Jackson Laboratories, ME, USA) with a T2D model: db/db mice purchased from Harlam Laboratories (Netherlands), as previously described (Ramos-Rodriguez et al., 2015b). Both T2D and AD are diseases closely associated with aging and in order to fully characterize these mice, animals were aged up to 36 weeks of age, when both pathologies are well-established.

All experimental

Metabolic characterization

As previously described, body weight was significantly increased in db/db and APP/PS1xdb/db mice up to 24 weeks whereas by 36 weeks of age we observed that body weight was no longer increased in APP/PS1xdb/db mice. We detected a significant genotype × age effect by 2-way ANOVA [F(6,35) = 9.79, **p < 0.01], and further differences were detected at selected time points by one-way ANOVA followed by Tukey B or Tamhane tests as required (week 12 [F(3,11) = 14.29, ††p < 0.01 vs. control and APP/PS1]), week 24 [

Discussion

Previous epidemiological and clinical studies (Ott et al., 1996, Luchsinger et al., 2007, Plastino et al., 2010), as well as animal models (Takeda et al., 2010, Niedowicz et al., 2014), have analyzed the close relationship between T2D and AD. Both are chronic diseases clearly associated with ageing and therefore it is of special relevance to study the long-term cross-talk between both pathologies. In order to further analyze this aspect we have characterized a complex animal model, that

Conflicts of interest

Authors have no conflicts of interest and funding sources are specified as required.

Authors contributions

CI-G, JJR-R and LG-G performed the experiments. CI-G, JJR-R and MGA analyzed and interpreted the data, MGA conceived the experiments and wrote the manuscript approved by authors.

Founding

Junta de Andalucia, Proyectos de Excelencia, Consejería de Economía, Innovación, Ciencia y Empleo (P11-CTS-7847), Fundacion Eugenio Rodriguez Pascual 2015, ISCIII–Subdirección General de Evaluación y Fomento de la Investigación, cofinanced by the European Union (Fondo Europeo de Desarrollo Regional, FEDER) “Una manera de hacer Europa” PI12/00675 (Monica Garcia-Alloza). Authors declare no conflicts of interest.

Acknowledgements

Junta de Andalucia, Proyectos de Excelencia, Consejería de Economía, Innovación, Ciencia y Empleo (P11-CTS-7847), Fundacion Eugenio Rodriguez Pascual 2015, ISCIII–Subdirección General de Evaluación y Fomento de la Investigación, cofinanced by the European Union (Fondo Europeo de Desarrollo Regional, FEDER) “Una manera de hacer Europa” PI12/00675 (Monica Garcia-Alloza). Authors declare no conflicts of interest.

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