A metabolic perspective of late onset Alzheimer’s disease

Abstract

After decades of research, the molecular neuropathology of Alzheimer’s disease (AD) is still one of the hot topics in biomedical sciences. Some studies suggest that soluble amyloid β (Aβ) oligomers act as causative agents in the development of AD and could be initiators of its complex neurodegenerative cascade. On the other hand, there is also evidence pointing to Aβ oligomers as mere aggravators, with an arguable role in the origin of the disease.

In this line of research, the relative contribution of soluble Aβ oligomers to neuronal damage associated with metabolic disorders such as Type 2 Diabetes Mellitus (T2DM) and obesity is being actively investigated. Some authors have proposed the endoplasmic reticulum (ER) stress and the induction of the unfolded protein response (UPR) as important mechanisms leading to an increase in Aβ production and the activation of neuroinflammatory processes. Following this line of thought, these mechanisms could also cause cognitive impairment.

The present review summarizes the current understanding on the neuropathological role of Aβ associated with metabolic alterations induced by an obesogenic high fat diet (HFD) intake. It is believed that the combination of these two elements has a synergic effect, leading to the impairement of ER and mitochondrial functions, glial reactivity status alteration and inhibition of insulin receptor (IR) signalling. All these metabolic alterations would favour neuronal malfunction and, eventually, neuronal death by apoptosis, hence causing cognitive impairment and laying the foundations for late-onset AD (LOAD).

Moreover, since drugs enhancing the activation of cerebral insulin pathway can constitute a suitable strategy for the prevention of AD, we also discuss the scope of therapeutic approaches such as intranasal administration of insulin in clinical trials with AD patients.

Introduction

The study of Alzheimer’s disease (AD) began in the early twentieth century, when the German physician Alois Alzheimer described the first case of this pathology in a 51-year old woman called Auguste Deter [1]. Her symptoms included remarkable memory loss, language difficulties and personality changes. After the post-mortem examination, the brain autopsy revealed specific neuropathological changes in the cerebral cortex [[1], [2], [3], [4]], now known as the classical morphological symptoms of AD: amyloid β (Aβ) peptide plaques derived of the activity of the amyloidogenic pathway and neurofibrillary tangles (NFTs), composed by hyperphosphorylated tau protein [[3], [4], [5], [6], [7], [8]].

At present, the aetiological hypothesis most supported by the scientific community is the “amyloid cascade hypothesis”, which is summarized in Fig. 1. According to this hypothesis, under physiological conditions amyloid β protein percussor (AβPP) is cleaved by the enzyme α-secretase, following the non-amyloidogenic pathway. This precludes formation of amyloidogenic peptides and leads to a release of secreted AβPP alpha (sAβPPα), which has neuroprotective properties [5]. On the contrary, in the amyloidogenic pathway, AβPP is cleaved by β-secretase (BACE-1) at N-terminus and, in turn, γ/ε-secretase cleaves it at the C-terminus to yield secreted AβPP (sAβPP), Aβ40/42 fragments (which remain in the extracellular space) and a C-terminal fragment with 99 amino acids (C99) that can be translocated to the nucleus. Here, it may induce expression of genes that promote neuronal death by apoptosis. Moreover, the soluble Aβ oligomers generated in this way affect synapse function, decrease neuronal plasticity, alter energy and glucose metabolism, induce oxidative stress and mitochondrial dysfunction, and disturb celular calcium homeostasis [2,5].

During the early 1990s, some genetic factors -apart from AβPP- were shown to increase the risk of developing the disease, such as apolipoprotein E (APOE) or presenilin 1 and 2 (PS1 and PS2) [[7], [8], [9], [10], [11]]. These factors were also involved in the amyloid cascade. For instance, the allele for APOE ε4 was been shown to impair Aβ clearance and promote its aggregation, leading to increased severity of this amyloid pathology [[7], [8], [9], [10], [11], [12]]. In spite of this, the existence of other factors that can contribute to the pathogenesis of AD emphasizes its complexity. Some of these risk factors are shown in Fig. 2.

Against this background, AD patients were classified into two groups. The first one was formed for those subjects that developed the pathology due to genetic causes leading to the production of classical biomarkers like Aβ. This group covered about 3% of AD patients and was dubbed “familial or early-onset AD”. The remaining 97% of patients were categorized as “sporadic or late-onset AD” (LOAD), whose progression was associated with advanced age, hypertension, hyperlipidaemia, coronary disease, obesity and type 2 diabetes mellitus (T2DM) [[12], [13], [14]].

T2DM is a complex disease with a chronic evolution that requires continuous medical care, mainly focused on the reduction of global cardiovascular risk, peripheral complications and cognitive loss [15]. Unlike type 1 diabetes mellitus (T1DM), an autoimmune disorder characterized by the selective destruction of insulin-producing β-cells [16,17], in T2DM there is an alteration in the mechanisms of uptake and/or secretion of insulin. This leads to a chronic increase in blood levels of glucose, resulting in a higher risk of macro and microvascular complications. T2DM is also associated with insulin resistance (IR), which is characterized by lower insulin activity at the cellular level, and affects the metabolism of carbohydrates, lipids and proteins [15]. As we have mentioned, in addition to a risk factor for cardiovascular pathologies, T2DM is also an independent risk factor for LOAD [[11], [12], [13], [14]]. Specifically, it is widely recognized that T2DM and AD share several kinds of abnormalities, including increased oxidative stress, impaired glucose metabolism and insulin resistance characterized by continuous hyperinsulinemia [12,12,13,14,18]. Likewise, some studies have focused on the role of insulin receptor (IR), which might be an important player in the pathology of AD, by contributing to the biochemical, molecular and histopathological characteristics of the pathology [13,[19], [20], [21], [22], [23], [24], [25], [26], [27]].

Given that the origin of the pathology is still unknown, and that there seem to be many players involved in its development, AD has been defined as a multifactorial disease (Fig. 2). Consequently, there are different research areas, in addition to neuroscience, trying to elucidate the origin of this pathology. In fact, prospective epidemiological studies have identified metabolic syndrome and T2MD as risk factors for multiple diseases of the nervous system [[18], [19], [20]]. Furthermore, animal studies have shown that hypercaloric diets affect the structure and functions of the hippocampus, although the specific mechanisms are unclear [28], [29]. Thus, it has been reported that AβPPswe/PS1dE9 (AβPP/PS1) transgenic mice fed with a diet enriched in palmitic acid, showed reduced IR and increased insoluble Aβ peptide levels, as well as cognitive deficits [30]. Moreover, Ho and colleagues found evidence linking insulin resistance and increased relative risk for AD neuropathology development, by demonstrating that IR signalling can influence Aβ production in the brain [31]. These results evidenced the relationship between metabolic alterations and progression of AD features, thus reinforcing the hypothesis of a metabolic aetiology of AD. Indeed, it has been proposed to re-name AD as “type 3 diabetes mellitus” (T3DM) or brain-specific diabetes [32].

The present review is a state-of-the-art about the relation among obesity, Aβ oligomers and the IR modulation. In addition, we discuss the potential application of drugs modulating the brain insulin receptor pathway as targets for AD prevention.