Insulin-like Growth Factor I in Sporadic Alzheimer’s Disease: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Jonathan A. Zegarra-Valdivia
,
Jaime Pignatelli
,
Angel Nuñez
,
Ignacio Torres Aleman

Despite decades of intense research, disease-modifying therapeutic approaches for Alzheimer’s disease (AD) are still very much needed. Apart from the extensively analyzed tau and amyloid pathological cascades, two promising avenues of research that may eventually identify new druggable targets for AD are based on a better understanding of the mechanisms of resilience and vulnerability to this condition. Insulin-like growth factor I (IGF-I) activity in the brain provides a common substrate for the mechanisms of resilience and vulnerability to AD. Preserved brain IGF-I activity contributes to resilience to AD pathology as this growth factor intervenes in all the major pathological cascades considered to be involved in AD, including metabolic impairment, altered proteostasis, and inflammation, to name the three that are considered to be the most important ones. 

  • Alzheimer’s disease
  • insulin-like growth factor I
  • AD

1. Introduction

Mutations in amyloid precursor protein (APP) and preselinins are associated with familial Alzheimer’s disease (fAD), which constitutes around 1% of Alzheimer’s disease (AD) cases [1], and are the cause of overproduction of amyloid β (Aβ) peptides [2][3]. Excess production and reduced clearance of Aβ peptides have been postulated for many years as the major pathogenic pathway in AD [4]. fAD patients usually start to show symptoms at around the fourth decade of life [5], which suggests that overproduction of Aβ over the decades is required to start AD symptoms. In sporadic AD (sAD) associated with old age, it is now considered that Aβ accumulation starts at least 20 years before AD symptoms become evident, at around >65 years of age [6]. Hence, apparently, fewer years of Aβ accumulation are required in sAD to develop symptoms, compared to fAD. Among several potential explanations, it might be that a younger brain combats Aβ accumulation more efficiently than an older brain, as specific mechanisms of resilience to cognitive deterioration have been described [7][8], which may weaken along with age. Alternatively, it is possible that in sAD, other pathogenic pathways contribute to Aβ accumulation to reach a pathological threshold earlier. This threshold is specific for each individual [9], and a sizable proportion of elders (around 30%) show Aβ accumulation without AD symptoms [10]. As sAD is considered a multifactorial disease resulting from genetic/environmental interactions [11], while the former are, at present, difficult to overcome, environmental risk factors are possible to curtail. Indeed, lifestyle interventions are now implemented in personalized medicine protocols for AD patients [12], and constitute the basis of current therapeutic proposals [13] apart from pharmacotherapy.

2. Insulin-Like Growth Factor I (IGF-I) and AD Resilience

The concept of AD resilience has been coined to explain the presence of AD pathology in cognitively intact individuals [14]. The specific mechanism underlying AD resilience is still undetermined and is often related to the concept of cognitive reserve (see below). Resilience to AD seems in part to be genetically determined as it shows a sex-dependent inheritable architecture [15], and this is not surprising considering the heavy genetic make-up of AD risk [16]. This genetic component may help uncover novel targets of resilience, such as the recently reported reelin, a protein functionally related to ApoE [17], a major genetic risk factor for sAD. However, the bulk of mechanisms of AD resilience are not genetic, and novel proposals are needed.
Accordingly, several lines of research are trying to shed light on AD resilience, as it appears very promising to develop novel routes of AD therapy. For example, early life context [18], aerobic glycolysis [19], efficient microglial phagocytosis [20], and dendritic spine plasticity [21] have all been suggested to contribute to resilience/vulnerability to AD. Therefore, understanding the underlying mechanisms will unveil new potential targets in AD prevention. In this vein, while no general consensus has yet been reached, and the major conclusions indicate that further work is needed to firmly establish a causal link between circulating IGF-I levels and cognition [22], available information allows us to suggest that preserved brain IGF-I activity also contributes to resilience to AD pathology. Thus, all the major characteristics found in individuals resilient to AD can be explained in the light of preserved brain IGF-I activity. These include conserved neuronal numbers, synaptic markers, and axonal architecture, as well as cytokine profiles consisting of higher anti-inflammatory signals and neurotrophic factors, and lower cytokine mediators of microglial recruitment [23][24].

Mechanisms of IGF-I-Dependent AD Resilience

Potentiation of neurotrophic activity, most often BDNF [25], has already been invoked as a mechanism of AD resilience [26], but specific mechanisms and factors need to be defined. Since the neuroprotective actions of IGF-I are pleiotropic [22][27], all the major characteristics found in AD resilience can be readily explained through them. These variety of IGF-I effects involve different pathways, as explained in detail elsewhere [28]. Importantly, other neurotrophic pleiotropic factors, such as melatonin, have also been implicated in AD resilience through longevity signals, such as Sirt1, or anti-inflammatory pathways involving NFκB [29]. Therefore, it is very likely that different neurotrophic activities, and not only IGF-I, are involved in resilience to AD.
As for the mechanisms underlying IGF-I-mediated AD resilience, scholars first focus on cell-based processes that affect all types of brain cells [30]. Among them, synapse loss is considered a major structural disturbance associated with cognitive deterioration in sAD [31]. Thus, IGF-I is involved in physiological synaptogenesis during development [32], in adult brains [33], and in synapse repletion after an insult [34]. Importantly, dendritic spines, a major site of cortical synapses, provide AD resilience [21], while IGF-I promotes dendritogenesis [35] and is intricately involved in synaptic physiology [36][37].
Another process that is emerging as an important event in cellular changes in AD is neuro-inflammation, classically associated with astrocytes and microglia as the main cellular effectors [38][39]. We must remember that inflammation is primarily a homeostatic response to pathology, and when it becomes maladaptive, for as yet poorly described reasons, it constitutes a key factor in driving sAD pathology [40][41], leading to the alteration of structural and functional brain networks seen in AD, as recently reported [42]. This “double-edge sword” process [43] is also modulated by IGF-I acting through a calcineurin-NFκB pathway in astrocytes that reversibly drives AD pathology in AD mice [44]. Naturally, neuro-inflammation also impacts on many other cellular activities, such as astrocyte phagocytosis [45], microglial reactivity [46] and proliferation [47], and activity of brain resident macrophages [48], and it also interacts with the brain angiotensin anti-inflammatory pathway [49][50]. The involvement of IGF-I in the response to neuro-inflammatory processes associated with brain damage in general attests to an important role of IGF-I in neuro-inflammation [49].
Other cell-associated processes in AD pathology, such as excess oxidative stress [51], which is probably directly involved in AD-related cell demise [52], are also counteracted by IGF-I [53]. Since an efficient mechanism of prevention of oxidative stress has been suggested to work in the brain of individuals showing AD resilience [54], antioxidant actions of IGF-I in brain tissue could be forming part of this resilience. Moreover, tau hyperphosphorylation in neurons, a hallmark of AD, can also be ameliorated by IGF-I through its capacity to inhibit tau kinases such as GSK-3 [55].
At the system level, dysregulated neural circuit activity [56][57] and an altered astrocytic network [58][59], or both disturbances interacting with each other [60][61], are postulated to participate in the initiation and maintenance of the AD pathogenic cascade. While diverse explanations have been proposed, including early alterations of peptidergic systems [62][63], tau accumulation [64], or early loss of inhibitory tone [65], impaired brain IGF-I activity may also be involved. Although the evidence is less robust than its relation to cell-based processes related to AD pathology, it is well documented that IGF-I regulates neuronal activity at various levels. Thus, IGF-I modulates neuronal excitability [36] and excitatory/inhibitory balance [66][67], which also includes its actions through astrocytes [68], a type of glial cell known to modulate neuronal circuits.

This entry is adapted from the peer-reviewed paper 10.3390/ijms242216440

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