Cite this asShafie NS, Morsy YM, Amer M (2023) Deciphering PPAR-inducing pathway clarifying the link between Alzheimer’s Disease and diabetes. Ann Pancreat Disord Treatm 5(1): 001-005. DOI: 10.17352/apdt.000010
Copyright© 2023 Shafie NS, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Diabetes is a widely prevalent metabolic disorder characterized by chronic hyperglycemia. This condition is caused by various factors that ultimately result in pancreatic β cell failure. The American Diabetes Association (ADA) recognizes two main types of diabetes: Type 1 diabetes mellitus (T1DM) and Type 2 diabetes mellitus (T2DM) [1-4]. In addition to Type 1 and Type 2 diabetes mellitus, there are two additional categories of Diabetes, namely Gestational Diabetes Mellitus (GDM) and monogenic diabetes.
The multisystemic nature of Diabetes implies that complications and comorbidities can impact multiple organ systems, especially critical organs such as the heart, brain, and kidneys, particularly when good glycemic control is not achieved . Furthermore, sleep apnea has been identified as a comorbidity of type 2 diabetes, as it is more prevalent in individuals with diabetes than in those without diabetes [6,7]. Long-term complications of diabetes are primarily the result of vascular damage, which can be categorized as either macrovascular or microvascular. Microvascular complications include diabetic retinopathy, diabetic nephropathy (the leading cause of death in diabetic patients), and diabetic peripheral neuropathy, which remains a leading cause of blindness, end-stage kidney disease, and lower limb amputation . Conversely, macrovascular complications are associated with an increased risk of coronary heart disease, peripheral vascular disease, cerebrovascular disease, and stroke . In addition to the complications mentioned, Previous studies have suggested a strong association between Type 2 diabetes mellitus and late-onset Alzheimer’s Disease (AD) [10-13].
The correlation between AD and T2DM is primarily due to their shared pathophysiological characteristics [14,15]. While the exact mechanisms are not fully understood, several key proteins have been proposed as potential factors, which will be discussed in detail in this review. Insulin-dependent Type 1 diabetes mellitus (T1DM) is a condition that is prevalent among a minority of diabetics, accounting for only 5% - 10% . The primary cause of T1DM is an autoimmune attack on the β cells .
Type 2 diabetes mellitus (T2DM) is an insulin-independent disorder that is prevalent among most diabetics, accounting for 90% - 95% of cases. The primary characteristic of T2DM is insulin resistance [18-21].
Alzheimer’s Disease (AD) is a neurodegenerative disorder that progresses gradually and is characterized by cognitive decline and memory loss [22,23]. Alzheimer’s Disease (AD) is the most prevalent form of dementia, accounting for 60% - 70% of all cases globally [24,25]. There is substantial evidence linking the pathogenesis of Alzheimer’s Disease (AD) to the deposition of amyloid-beta (Aβ) plaques and hyperphosphorylation of tau protein leading to neurofibrillary tangles [26-28].
However, the exact etiological factors/mechanisms and pathogenesis of AD remain uncertain [29,30]. While the accumulation of Aβ42 alone cannot fully account for the sequence of pathological events observed in Alzheimer’s Disease (AD), it can be attributed to dysregulated insulin/IGF-1 signaling [31-33].
New findings indicate a close link between insulin resistance and Alzheimer’s Disease, similar to the case of chronic type 2 diabetes mellitus (T2DM) [31,34-37]. Epidemiological studies conducted over the past several decades have explored the correlation between changes in IR/IGF-R signaling pathways and other proteins associated with insulin signaling and Alzheimer’s Disease (AD). These studies suggest that there may be a relationship between these factors [7-13]. Despite extensive research, there are still unanswered questions regarding the interaction between T2DM and AD and how precisely T2DM influences the development of AD. Addressing these questions may provide valuable insights and guide the development of more effective therapeutic strategies.
Traditionally, the brain has been regarded as insulin-insensitive because insulin does not stimulate glucose metabolism in the brain [38,39]. It has been reported in recent studies that there are high densities of insulin receptors present in the brain . According to these studies, the regulation of peripheral energy homeostasis is influenced by the hypothalamic action of insulin . Insulin signaling has been shown to play a crucial role in various processes within the brain, including development, neuroprotection, metabolism, plasticity, and promotion of brain Aβ clearance. However, it also plays a significant role in neurodegeneration and neuropathological processes, such as cognitive decline and the development of Alzheimer’s Disease [40-42]. Therefore, the notion that Alzheimer’s Disease (AD) could be classified as type 3 diabetes has gained considerable support [43-46].
Alzheimer’s Disease, along with several other neurodegenerative diseases, displays neuro-inflammation as an early and consistent feature. [47,48]. The high expression of pro-inflammatory cytokines, including IL-1β and IL-6, provides further support for this association [47,49]. Consequently, these changes can lead to behavioral alterations, neuronal death, and accelerated disease progression. Furthermore, the increased expression of interferon-gamma and macrophage migration inhibitory factors in proximity to Aβ42 plaques can cause direct neuronal damage and death, as observed in the AD brain [47,48,50].
Peroxisome Proliferator-Activated Receptors (PPARs) participate in various molecular and enzymatic pathways that are DNA-dependent and independent in adipose tissue, liver, and skeletal muscles . These pathways are disrupted in disease states and can lead to metabolic energy imbalances . Hence, targeting PPARs can serve as a potential therapeutic strategy for a wide range of diseases, including but not limited to diabetes, obesity, inflammation, neurodegenerative disorders, and cancer [53-55]. PPARs have been found to play a role in regulating insulin-stimulated gene expression by sensing signals transmitted from cell surface membranes .
PPARs consist of three isoforms, which are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily [52,57,58]. The brain expresses all three isoforms of PPARs, with PPARβ/δ exclusively expressed in neurons and PPARα and γ expressed in both neurons and astrocytes . PPARα is responsible for regulating energy homeostasis, while the activation of PPARγ leads to insulin sensitization and enhanced glucose metabolism. On the other hand, the activation of PPARβ/δ is associated with enhanced fatty acid metabolism. Therefore, the PPAR family is known to play a significant role in regulating energy homeostasis and metabolic function, in addition to its potent anti-inflammatory effects .
The downregulation of PPAR-β/δ in the brain is an AD-related abnormality that can be associated with both insulin resistance and neuroinflammation. PPAR-β/δ is highly expressed in the normal brain, like PPAR-α, while the gene expression of PPAR-γ is upregulated . Moreover, experimental studies have shown that the depletion of PPAR- β/δ not only leads to an increase in neuroinflammation but also causes oxidative stress, astrogliosis and the deposition of Aβ42 and PHF tau in the brain  (Figure 1).
Insulin resistance (IR) in Type 2 diabetes (T2D) contributes to the formation of both Aβ plaques and tau hyperphosphorylation. Tau protein becomes hyperphosphorylated, detaches from microtubules, aggregates to neuronal fibrillary tangles. Additionally, the deposition of amyloid plaques triggers the release of proinflammatory responses such as IL-6, TNF-α, IFN-γ, and IL-α, leading to neuroinflammation and promoting neuronal injury. The combined effect of these factors leaves neurons vulnerable to various attacks, resulting in the gradual loss of synapses and eventually neuronal death. The accompanying figure illustrates the potential impact of PPAR-β/δ depletion on neuroinflammation and neurodegenerative disorders, including Alzheimer’s.
The dashed arrows suggest that the relationship between T2D and AD is likely bidirectional, although the precise mechanism is unclear. The arrows next to the gene names or biological processes indicate the effects of IR, with up-arrows indicating elevated/up-regulated genes or processes and down-arrows indicating down-regulated genes or processes. The different colors denote distinct roles in AD, with pink indicating the role of IR in AD and blue indicating the role of PPAR-β/δ in AD.
Awareness of the critical role of insulin in the brain and the insulin resistance observed in AD has led to attempts to overcome impaired insulin signaling and improve brain IR sensitivity. One approach is to use insulin sensitizers such as Peroxisome Proliferator-Activated Receptor (PPAR) agonists, which have shown promising early therapeutic effects on AD-associated molecular and biochemical brain pathologies [59,61, 62].
PPAR-β/δ agonist has been shown to effectively reduce astrocyte activation, providing an anti-inflammatory effect on glial cells. It also reduces neutrophil infiltration into the brain during ischemia and provides protection against neuroinflammation [56,63]. Studies have reported that PPAR-β/δ agonist has the ability to reduce amyloid burden, which includes Aβ42 deposition, and this effect may be mediated by its impact on amyloid clearance [56,64]. Aβ-oligomers can induce neuronal insulin resistance by promoting TNF-α secretion, leading to the activation of stress kinases IκB kinase (IKK) and double-stranded RNA-dependent protein kinase (PKR) [65,66].
This activation has been observed in AD animal models and can induce inflammation and endoplasmic reticulum stress, as well as deregulation of insulin signaling . Together, these data suggest a feed-forward loop where Aβ oligomers amplify brain IR, which further decreases Aβ clearance and enhances the predisposition for Aβ oligomerization .
Collectively, the evidence supports the notion that insulin resistance plays a significant role in the pathogenesis of AD, leading to neuroinflammation and ultimately neurodegeneration. Early treatment with insulin sensitizers such as PPAR agonists, which possess both anti-inflammatory and neuroprotective properties, holds promise as a therapeutic strategy for mitigating AD and other neurodegenerative disorders.
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