Elsevier

Psychoneuroendocrinology

Volume 62, December 2015, Pages 69-79
Psychoneuroendocrinology

Central vascular disease and exacerbated pathology in a mixed model of type 2 diabetes and Alzheimer's disease

https://doi.org/10.1016/j.psyneuen.2015.07.606Get rights and content

Highlights

  • Central alterations are synergistically worsened in APP/PS1xdb/db mice.

  • Early central atrophy, tau pathology and inflammation is detected in APP/PS1xdb/db mice.

  • APP/PS1xdb/db mice show a shift in soluble/insoluble Aβ levels towards more toxic soluble species.

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

  • Cognition is severely impaired in APP/PS1xdb/db mice in an age dependent manner.

Abstract

Aging remains the main risk factor to suffer Alzheimer's disease (AD), though epidemiological studies also support that type 2 diabetes (T2D) is a major contributor. In order to explore the close relationship between both pathologies we have developed an animal model presenting both AD and T2D, by crossing APP/PS1 mice (AD model) with db/db mice (T2D model). We traced metabolic and cognitive evolution before T2D or AD pathology is present (4 weeks of age), when T2D has debuted but no senile plaques are present (14 weeks of age) and when both pathologies are well established (26 weeks of age). APP/PS1xdb/db mice showed an age-dependent synergistic effect between T2D and AD. Significant brain atrophy and tau pathology were detected in the cortex by 14 weeks, that spread to the hippocampus by 26 weeks of age. Severe cognitive impairment was also detected as soon as at 14 weeks of age. Interestingly, in APP/PS1xdb/db mice we observed a shift in Aβ soluble/insoluble levels, and whereas more toxic soluble species were favoured, senile plaques (SP) were reduced. An overall increase of microglia activation was observed in APP/PS1xdb/db mice. We also found exacerbated hemorrhagic burden in APP/PS1xdbd/db mice, suggesting that blood brain barrier alterations may be responsible for the early pathological features observed. Moreover, metabolic parameters can predict many of these alterations, supporting a role for T2D in AD pathology. This new model provides a relevant tool to further explore the relationship between T2D, AD and vascular implications, offering the possibility to assess therapeutic approaches, that by improving T2D metabolic control could delay or prevent AD pathology.

Introduction

Alzheimer's disease (AD) is the most common cause of dementia in elderly people. Neuropathological features include senile plaques (SP), mainly composed of amyloid-beta (Aβ) peptide, neurofibrillary tangles, with increased phosphorylated tau, and neuronal and synaptic loss (Serrano-Pozo et al., 2011). Vascular dementia (VaD) is the second most common cause of the dementia, and it is an heterogeneous pathology ranging from multiple microinfarcts to small vessel ischemic disease or microvascular injury (Craft, 2009). In many patients, markers of vascular injury coexist with traditional AD hallmarks, blurring the borderlines between AD and VaD (Craft, 2009). Thus, AD features might be promoted by a specific form of vascular injury; for example, blood brain barrier (BBB) dysfunction may affect Aβ transport between brain and periphery, and thereby contribute to parenchymal and neurovascular Aβ deposition (Weller et al., 2008, Craft, 2009, Garcia-Alloza et al., 2011). On the other hand, AD pathology may cause vascular injury, as when Aβ-induced inflammation damages the endothelium.

The vast majority of AD cases are sporadic and the ultimate neurotoxic mechanisms have not been elucidated, however it seems that type 2 diabetes (T2D) may play a relevant role in the development of AD (Ott et al., 1996, Luchsinger et al., 2004, Plastino et al., 2010). Some relevant links between T2D and AD include the following: Impaired insulin secretion and resistance, as well as glucose intolerance seem to be associated with increased risk of AD (Ott et al., 1996, Ott et al., 1999, Plastino et al., 2010). In this sense, tight regulation of insulin levels seems to be mandatory to regulate central function. Central nervous system insulin receptors are highly expressed in regions associated to learning and memory, such as the cortex and the hippocampus and previous studies have reported that cognition impairment detected in type 1 diabetic children, might be related to hypoinsulinemia (Northam et al., 2001, Schoenle et al., 2002). Also, AD brains present lower insulin levels and higher insulin receptors density when compared to control patients (for review see (El Khoury et al., 2014)). On the other hand, hyperinsulinemia, as present at early stages of T2D, may alter Aβ levels by indirect mechanisms, like exacerbation of inflammatory responses that interact with Aβ processing and deposition (for review see (Bosco et al., 2011, Garcia-Alloza, 2014)). Other AD neuropathological features, such as tau phosphorylation, are also severely affected when insulin levels are altered, both in hyper and hypoinsulinemic situations (Clodfelder-Miller et al., 2006, Kim et al., 2009, Ramos-Rodriguez et al., 2013b, Ramos-Rodriguez et al., 2014). Insulin and Aβ are degraded by the same two proteases, neprilysin (NEP) and insulin degrading enzyme (IDE), and thus, direct substrate competition may alter regular proteolysis of both insulin and Aβ (Farris et al., 2003, Liu et al., 2010), and possibly influence the pathogenesis of AD and T2D (Gotz et al., 2009). Additionally, insulin participates in neurovascular regulation, linking metabolic disorders to VaD associated pathology (Correia et al., 2011), and vascular damage has been suggested to reduce Aβ clearance along interstitial fluid drainage pathways (Weller et al., 2008, Garcia-Alloza et al., 2011). Albeit all the circumstantial links mentioned above, experimental data supporting a direct relationship between T2D, AD and VaD are limited, mostly because T2D is a complex disorder and so, it is likely that multiple synergistic processes participate in AD pathology (Strachan et al., 2008). Also, animal models harbouring both, T2D and AD are scarce (Takeda et al., 2010, Niedowicz et al., 2014). Therefore we have developed and characterized a mixed model resulting from a cross between AD (APP/PS1) and T2D (db/db) mice at three different time-points: at 4 weeks of age, before AD pathological hallmarks are present and T2D symptoms have not yet appeared; at 14 weeks of age, when T2D has debuted but Aβ pathology is only incipient, and at 26 weeks of age when both pathologies are present and chronic. To our knowledge, the evolution of this relationship as diseases progress has not been studied. We have observed a synergistic effect between both pathologies in an age-dependent manner, and significant brain atrophy, tau pathology and cognitive impairment were detected in the APP/PS1xdb/db mice. Interestingly, a shift in Aβ soluble/insoluble levels was observed, with increased soluble toxic species found in APP/PS1xdb/db mice, accompanied by reduced insoluble Aβ and SP. Also, increased microglia activation, in SP-free areas, and hemorrhage burden was observed, suggesting that inflammatory processes and alterations in the BBB may be responsible for the pathological features detected in our mixed model of T2D and AD.

Section snippets

Animals

APP/PS1xdbdb mice were produced by cross-breeding an AD model: APPswe/PS1dE9 mice (APP/PS1) (Jackson Laboratories, ME, USA) with a T2D model: db/db mice purchased from Harlan Laboratories (Netherlands). APP/PS1 mice overexpress the Swedish mutation of APP in combination with a deletion of exon dE9 from PS1 (Jankowsky et al., 2004) and present amyloid deposition by 4 months of age in heterozygosis (Garcia-Alloza et al., 2006). On the other hand, db/db mice, are a functional knock out of the

T2D progression in APP/PS1xdb/db mice

Metabolic parameters were altered in db/db mice and this effect was worsened in the presence of the APP/PS1 transgenes. Body weight was increased in diabetic mice (both db/db and APP/PS1xdb/db) but it exceeded in APP/PS1 mice at 4 weeks of age (4 weeks: [F(3,54) = 4.205, **p = 0.01 vs. rest of the groups], 14 weeks [F(3,68) = 64.172, ††p < 0.01 vs. Control and APP/PS1 groups] and 26 weeks [F(3,81) = 168.926, **p < 0.01 vs. Control and APP/PS1 groups]) (Fig. 1a and c). Whereas glucose levels were not

Discussion

The close relationship between AD and T2D has been widely reviewed in recent years (Craft, 2009, De Felice, 2013) and many epidemiological studies support the cross-talk between both pathologies (Ott et al., 1996, Luchsinger et al., 2007, Plastino et al., 2010, Schrijvers et al., 2010). However, studies on the underlying mechanisms, or the role of T2D in AD pathology are still scarce (Takeda et al., 2010, Niedowicz et al., 2014). Since both T2D and AD are chronic diseases associated with aging

Conflicts of interest

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

Authors contributions

JJR-R, MJ-P, MIM-C, CI-G and FH-P performed and analyzed the experiments. EB analyzed and interpreted data, AML-S conceived the experiments and reviewed the manuscript, IC-C conceived and performed the experiments, and reviewed the manuscript. MG-A conceived and performed the experiments, analyzed and interpreted the data, and wrote the manuscript approved by authors.

Acknowledgements:

Junta de Andalucia, Proyectos de Excelencia, Consejería de Economía, Innovación, Ciencia y Empleo (P11-CTS-7847), Fundación Eugenio Rodríguez Pascual 2015, ISCIII–Subdirección General de Evaluación y Fomento de la Investigación and 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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