Insulin-degrading enzyme: Roles and pathways in ameliorating cognitive impairment associated with Alzheimer's disease and diabetes

Accumulation of amyloid-β in the central nervous system is a common feature of Alzheimer's disease (AD) and diabetes-related cognitive impairment. Since the insulin-degrading enzyme (IDE) can break down amyloid-β plaques, there is considerable interest in using this enzyme to treat both neurological disorders. In this review, we have summarized the pre-clinical and clinical research on the potential application of IDE for the improvement of cognitive impairment. Furthermore, we have presented an overview of the main pathways that can be targeted to mitigate the progression of AD and the cognitive impairment caused by diabetes.


Introduction
Insulin-degrading enzyme (IDE), as the name implies, has a high affinity for insulin (K m ≈14 nM) (Gonzalez-Casimiro et al., 2021), and its upregulation can decrease insulin levels, leading to elevated blood glucose levels. In contrast, downregulation of IDE may reduce insulin degradation and maintain normal blood glucose levels. Additionally, IDE can degrade other proteins, including islet amyloid polypeptide (IAPP) (Bennett et al., 2000), glucagon (Ansorge et al., 1984), insulin-like growth factor-I (IGF-1) (Roth et al., 1984), insulin-like growth factor-II (IGF-2) (Roth et al., 1984) and amyloid-β (Aβ) (Kurochkin, Goto, 1994). Notably, IDE appears crucial for treating impairments associated with Aβ accumulation in the brain in Alzheimer's disease (AD) and diabetic cognitive impairment (Hamze et al., 2022). Thus, upregulation of IDE in the central nervous system (CNS) may stimulate the breakdown of Aβ plaques in the brain tissues and alleviate the associated cognitive deficits. Here, we discuss the ameliorative effects of IDE on AD and diabetes-related cognitive impairment and the potential pathways involved in this process.

Accumulation of Aβ in the CNS
The etiological basis of cognitive impairment in AD and diabetes is the accumulation of Aβ in the CNS tissues. Due to this similarity, some researchers have classified AD as "type 3 diabetes" (Michailidis et al., 2022). Given the dual action of IDE against insulin and Aβ, it is increasingly being considered for the treatment of AD-related and diabetes-related cognitive impairment. The research conducted so far on the potential therapeutic effects of IDE has been explored in greater detail in the following sections.

Impaired insulin-related signaling pathways
The insulin-related signaling pathways are disrupted in diabetes, resulting in the onset of insulin resistance (Biessels, Reagan, 2015). Likewise, the insulin signaling pathway in the CNS is also impaired during the progression of AD (Kullmann et al., 2016). The current consensus is that the impairment of peripheral and central insulin-related signaling pathways at the onset of diabetes and AD respectively can lead to cognitive impairment.

Insulin resistance and hyperinsulinemia
Insulin resistance refers to the decreased sensitivity of target tissues to the action of insulin, which reduces the ability of insulin to regulate glucose metabolism, eventually resulting in elevated blood glucose. The pancreas then secretes more insulin to lower blood glucose levels, leading to insulin accumulation and hyperinsulinemia. Therefore, insulin resistance is an important cause of hyperinsulinemia (De Felice et al., 2022;Jeong et al., 2018).
Insulin is present within both the central and peripheral systems, and passes into the CNS from the bloodstream by crossing the blood-brain barrier (Biessels, Reagan, 2015). Therefore, insulin resistance and hyperinsulinemia can occur in both the central and peripheral systems, and there is evidence that the interaction between insulin resistance in the CNS and periphery might be involved in the development of AD and diabetic cognitive impairment (Kellar, Craft, 2020). For example, brain imaging studies on patients with insulin resistance has shown extensive axonal damage in the white matter, which can lead to cognitive impairment (Ryu et al., 2014). Furthermore, diabetic patients on long-term insulin therapy have a higher risk of cognitive impairment, which may be caused by chronic fluctuations in blood glucose and insulin, or even hyperinsulinemia (Ott et al., 1999). There is evidence that hyperinsulinemia resulting from insulin resistance leads to neuronal damage and defective synaptic plasticity in the hippocampus, increases the likelihood of neuroinflammation and neurodegeneration, and even triggers the production and accumulation of Aβ and tau protein in the brain tissues, all of which contribute to the onset of cognitive impairment (Arnold et al., 2018;Cater, Holter, 2022;Dutta et al., 2022).
Taken together, the accumulation of Aβ plaques in the brain, insulin resistance and hyperinsulinemia may be the common pathological drivers of cognitive impairment linked to diabetes and AD (Fig. 1). Therefore, pharmacological interventions that regulate IDE expression and reduce Aβ accumulation in the CNS can mitigate cognitive impairment, which will be discussed in the subsequent sections.

Diabetes raises the possibility of cognitive impairment
Diabetes is a prevalent chronic illness that currently ranks as the fourth most common cause of disability, and it is projected to become the seventh leading cause of mortality worldwide by 2040. The continuous increase in the incidence of diabetes will significantly affect public health, living costs, and the quality of life (Collaboration, 2016;Magliano et al., 2021).
Diabetic encephalopathy is a frequent complication of diabetes and causes cognitive impairment. In fact, studies have consistently shown that diabetic patients are more likely to exhibit symptoms of significant cognitive impairment, and the older diabetics have a 1.5-2 times higher risk of impaired cognition compared to age-matched healthy controls (Biessels, Despa, 2018;Srikanth et al., 2020). Furthermore, diabetic patients are also 1.53 times more likely to develop dementia from mild cognitive impairment (MCI) (Xue et al., 2019), and have a 100-150% greater risk of developing vascular dementia, along with 50-100% higher risk of AD (Gudala et al., 2013;Zhang et al., 2017). Diabetes-related cognitive impairment is characterized by hyperglycemia (Geijselaers et al., 2015;Rawlings et al., 2017), Aβ accumulation (Biessels, Despa, 2018), and hyperphosphorylation of tau protein (Motta et al., 2021).

Clinical research
A recent study (Sun et al., 2016) showed that serum IDE level was significantly lower, and the homeostasis model of assessment for insulin resistance (HOMA-IR) level was significantly higher in diabetic patients with MCI compared to the cognitively normal patients. In addition, the IDE level was positively correlated with the Montreal Cognitive Assessment (MoCA) score, which suggests that the pathogenesis of diabetes-related cognitive impairment is dependent on both IDE levels and insulin resistance. However, most clinical studies have been limited to phenotypic assessment based on serum or plasma tests, and the mechanisms have not been explored due to technical constraints and ethical concerns. Therefore, pharmacological interventions that can prevent diabetes-related cognitive impairment through modification of IDE have been studied in experimental animal models.

Pre-clinical research
An early study showed that IDE activity and mRNA levels were significantly reduced in the cerebral cortex of streptozotocin (STZ)induced diabetic rats, which increased Aβ deposition in the brain tissues (Liu et al., 2011). In the GK diabetic rat model  as well, missense mutations in IDE decreased insulin levels and Aβ degradation in the brain tissues. In addition, Aβx-40 and Aβx-42 aggregates increased significantly in the primary neuronal cells of IDE mutant rats after 4 and 7 days of culture. These studies strongly suggest the involvement of IDE in the onset of cognitive impairment, and raise the possibility that pharmacological activation of IDE may accelerate the degradation of Aβ and alleviate cognitive impairment.
One study showed that geniposide significantly decreased blood glucose, total cholesterol (TC) and triglyceride (TG) levels in rats with STZ-induced diabetes and partially alleviated diabetic symptoms, which was accompanied by an increase in IDE levels and a significant reduction of Aβ1-42 in the hippocampus (Liu et al., 2013). Likewise, continuous geniposide gavage for 4 weeks in the amyloid precursor protein (APP) transgenic mice with STZ-induced diabetes significantly increased IDE expression, and decreased that of Aβ1-40, Aβ1-42 and APP in the brain tissues . However, neither study performed behavioral tests to link IDE modification with changes in cognitive function.
High fat diet (HFD)-fed mice treated with 4,5-dicaffeyolquinic acid (4,5-diCQA), the primary active component of Artemisia argyi, exhibited improvement in diabetes-related symptoms and glucose tolerance, along with a significant decrease in TG, TC and low-density lipoprotein cholesterol (LDLC) levels. Furthermore, 4,5-diCQA also upregulated the IDE protein, and decreased the expression of Aβ and caspase-3 in the brain tissues of model mice, all of which were critical in reversing the cognitive impairment induced by HFD feeding. Furthermore, the protective effects of 4,5-diCQA are likely mediated by the protein kinase B (Akt)/ glycogen synthase kinase-3β (GSK-3β) pathway (Kang et al., 2019).
The pre-clinical research studies have been summarized in Table 1. These studies mainly analyzed the effect of pharmacological therapies on diabetic cognitive impairment on the basis of the changes in peripheral blood glucose and central IDE levels. However, the modulatory effects of pharmacological intervention on the peripheral IDE levels, and the mechanisms underlying blood glucose control have not been completely elucidated. Future studies should focus on the interactions between IDE, blood glucose and Aβ in order to identify pathways that mediate cognitive impairment associated with diabetes.

Pathological features of AD
AD is the main contributor to dementia and the main cause of cognitive decline in the elderly. The prevalence of AD is rising annually due to an aging population, and is now one of the top 10 causes of death of people globally, along with other forms of dementia (Jeremic et al., 2021;Kalaria et al., 2008).
The primary pathological characteristic of AD is the development of Aβ plaques and neurofibrillary tangles (NFT) in the brain (Selkoe, Podlisny, 2002;Walsh, Selkoe, 2004;Yang, Song, 2013). The peptide Aβ, which is formed from APP (Baker-Nigh et al., 2015;Walsh et al., 2000), slowly polymerizes and accumulates in the brain, particularly in neuronal cells, resulting in synaptic damage and neuronal dysfunction (Bayer, Wirths, 2010;Sannerud et al., 2016). Accumulation of Aβ in the brain eventually leads to the formation of amyloid plaques, which exacerbates cognitive impairment (Dodart et al., 2002;McLean et al., 1999). Therefore, Aβ degradation is increasingly being considered as a potential therapeutic option against AD (Picone et al., 2020). Nevertheless, the treatment of AD is complicated by the incomplete spatial overlap between NFT and Aβ plaques in the brain (Delacourte et al., 2002;Jack et al., 2013;Morris et al., 2014).

Clinical research
One clinical study reported significantly lower serum IDE activity in the elderly patients with AD and MCI compared to age-matched healthy Fig. 1. Common features of AD and diabetes-related cognitive impairment. The accumulation of Aβ in the brain, impaired insulin-related pathways, insulin resistance, and hyperinsulinemia are observed in both AD and diabetes-related cognitive impairment, indicating that these features may be common pathogenic mechanisms in the two conditions. Abbreviations: Aβ, amyloid-β; AD, Alzheimer's disease. Abbreviations: 4,5-diCQA, 4,5-dicaffeyolquinic acid; Aβ, amyloid-β; APP, amyloid precursor protein; HFD, high fat diet; IDE, insulin-degrading enzyme; LDLC, low-density lipoprotein cholesterol; SD, Sprague Dawley; STZ, streptozotocin; TC, total cholesterol; TG, triglyceride.
individuals (Liu et al., 2012). The lower activity IDE may lead to the accumulation of Aβ due to inefficient degradation. In another clinical study (Zhao et al., 2007), membrane-bound IDE protein expression and insulin degradation were both found to be significantly reduced in the hippocampus of elderly patients with MCI and AD, and were negatively correlated with the severity of cognitive impairment, as well as the amount of Aβx-42 aggregates in the brain. This study provided a more direct evidence of the relationship between IDE and Aβ underlying cognitive impairment in individuals with MCI, or those who are at high risk of developing AD. Therefore, it is reasonable to surmise that augmentation of IDE activity in patients with MCI can prevent accumulation of Aβ in brain tissues, and stall the development of AD.

Pre-clinical research
To investigate the impact of TGF-β1 on IDE, Lifshitz et al. (Lifshitz et al., 2013) generated transgenic mice overexpressing TGF-β1 in vivo by breeding heterozygous TGF-β1 mice (obtained from the Tony Wyss-Coray laboratory) harboring the inbred C57BL/6 genetic background. The results revealed that TGF-β1 mice had a significant (40%) reduction in brain IDE activity compared to healthy control mice. Moreover, the brain slices from TGF-β1 mice showed a remarkably higher amyloid deposition than those from healthy control mice. Furthermore, the mRNA expression of IDE was significantly decreased in bEnd5 cells (a representative of brain endothelial cells) treated with 10 ng/ml TGF-β1. These findings suggest that TGF-β1 could be a crucial element contributing to the reduction in IDE expression and activity in the brain, potentially leading to the accumulation of amyloid in the brain.
Previous studies have shown that TGF-β1 can stimulate the production of extracellular matrix proteins, which is related to the cerebrovascular pathology of AD. For instance, amyloidosis of the cerebral vasculature is directly related to higher TGF-β1 levels in the brains of AD patients. Furthermore, perivascular amyloid deposition and perivascular astrocyte proliferation have been observed in the brains of TGF-β1 transgenic mice (BALB/c genetic background), which are closely linked to the onset of AD and other age-related neurodegenerative disorders (Wyss-Coray et al., 1995;Wyss-Coray et al., 2000;Wyss-Coray et al., 1997).
Taken together, these studies indicate that TGF-β1 is a reliable indicator of IDE activity and amyloid deposition, and a key factor in the signaling pathways involved in IDE-mediated degradation of amyloid.
Several studies have shown that pharmacological interventions that improve cognitive function in animal models of AD are correlated to elevated IDE expression, increased Aβ degradation, and reduction of Aβ and APP expression in brain tissues Liu et al., 2015;Shin et al., 2014). The mechanisms involved in the aforementioned studies have been summarized in Table 2, and are limited to changes in the levels of IDE, Aβ and APP.
To gain more detailed insights into the potential mechanisms involved in IDE-dependent improvement of cognitive function, several groups have treated animal models of AD (mainly Wistar rats) through intracerebroventricular (ICV) drug injections (Akhtar et al., 2021;Omar et al., 2022;Shingo et al., 2013;Wang et al., 2017). As shown in Table 3, the different pharmacological interventions significantly improved the cognitive function of the AD model by upregulating IDE, increasing Aβ degradation, and reversing neuronal loss in the hippocampal region. Furthermore, the reduction of neuronal damage in the hippocampus was correlated with the effects of the respective drugs of IDE and Aβ deposition. This is consistent with the fact that accumulation of Aβ within neuronal cells leads to synaptic damage and neuronal dysfunction. The regulatory mechanisms involving IDE expression, Aβ degradation and neuronal damage need to be investigated further.
Activation of microglia and astrocytes can induce the secretion of IDE, which promotes clearance of Aβ deposits (Kong et al., 2010;Son et al., 2015). In neurodegenerative diseases, microglia exist in the active secretory state that can produce a large number of vesicular bodies, and can internalize membrane-bound IDE into luminal vesicles. Secretion of these vesicles containing IDE can clear the accumulated Aβ outside the cells (Corraliza-Gomez et al., 2022). Furthermore, glial cells can also directly bind to and phagocytose Aβ, thus lowering the amount of Aβ aggregates (Prinz et al., 2021). A recent study showed that spleen tyrosine kinase (SYK) signaling regulates microglia proliferation and their binding to Aβ during the pathogenesis of AD. Loss of SYK signaling increased accumulation of Aβ in the cerebral cortex and hippocampus of mice, which may be attributed to genetic changes in the microglia that impair their phagocytic ability (Ennerfelt et al., 2022). In addition, while normal astrocytes are known to absorb and clear Aβ aggregates, reactive astrocytes formed in response to cellular damage or toxic molecules in pathological states (Escartin et al., 2021) lack this ability (Ju et al., 2022).
Through a review of the above studies, we found that some studies have shown that pharmacological interventions in murine AD models can promote the secretion of IDE and the degradation of Aβ in the brain by inhibiting the overactivation of glial cells and production of inflammatory factors. On the other hand, there is evidence that the activation of glial cells during the pathogenesis of AD can promote clearance of Aβ Table 2 The probable role of IDE in improving AD (exploration of superficial mechanisms).

Table 3
The probable role of IDE in improving AD (ICV drug injection).  (Table 4) have also shown that pharmacological interventions can increase nerve growth factor (NGF) levels in the hippocampal tissues, which promotes hippocampal neurogenesis and improves cognitive function (Tsai-Teng et al., 2016;Yang et al., 2020a). Based on this, we hypothesized that increasing IDE expression in the brain and promoting Aβ degradation may enhance NGF expression, resulting in increased density of hippocampal neurons and improvement in cognitive function. Thus, the interactions between IDE, Aβ and NGF may be crucial for the treatment of AD.

Methods of Models Medicines and methods of intervention
According to clinical studies, patients with diabetic cognitive impairment and those with AD present reduced levels of serum IDE, although the exact mechanism is unclear at present. Multiple pathways may link low serum IDE levels with cognitive impairment, and affect insulin metabolism or Aβ degradation in the brain. However, given the limitations of clinical trials on human subjects, we have to rely on preclinical research to evaluate the effects of the changes in IDE levels on central insulin and Aβ degradation. So far, studies on animal models of AD suggest that promoting IDE expression in the brain can reduce Aβ accumulation and improve cognitive function. In the following sections, the relevant signaling pathways that may be involved in the therapeutic effects of IDE are discussed in further detail.

PI3K/Akt/GSK-3β signaling pathway
Under physiological conditions, insulin binds to the insulin receptor (IR), resulting in the phosphorylation of IR and the insulin receptor substrate (IRS). The phosphorylated IRS activates phosphoinositide 3-kinase (PI3K) and Akt, resulting in activation of the PI3K/Akt signaling pathway. GSK-3β, a downstream substrate of PI3K/Akt, is simultaneously inhibited. Any disruption in this signaling cascade may lead to the development of insulin resistance (Kim, Feldman, 2012;Mittal et al., 2016). AD patients frequently present with intracerebral metabolic disorders, which are the result of impaired insulin signaling and insulin resistance within the CNS (Chen, Zhong, 2013;Talbot et al., 2012). Therefore, it is worth investigating whether the degradation of Aβ in the brain by IDE depends on the PI3K/Akt/GSK-3β pathway. The schematic illustration of PI3K/Akt/GSK-3β signaling pathway is shown in Fig. 2 A. Administration of bis ethylmaltolato oxidovanadium (BEOV) in the APP transgenic mice significantly increased the expression of phosphorylated PI3K (p-PI3K) and phosphorylated Akt (p-Akt), and decreased that of phosphorylated GSK-3β (p-GSK-3β) in the brain. This led to a significant increase in IDE levels, which was accompanied by reduction in Aβ and phosphorylated tau (p-tau) protein levels, and improved cognitive function in the mice (He et al., 2020). In another study, AD was induced in albino adult mice through intracerebral injection of STZ, and cognitive impairment was confirmed on the basis of the Morris water maze test. In addition, the modeled mice had significantly lower levels of p-PI3K, p-Akt and p-GSK-3β in the hippocampus, and higher levels of p-tau and Aβ1-42 compared to normal mice. Treatment with pioglitazone and a kefir-derived probiotic reversed these changes (El Sayed et al., 2021).
Akhtar et al. successfully established a model of AD in Wistar rats by injecting STZ via the intracerebroventricular route, and found that oral administration of sodium orthovanadate (SOV) significantly improved their cognitive performance. At the molecular level, SOV activated the PI3K/Akt/GSK-3β pathway, which led to a significant increase in IDE levels in the brain. In addition, SOV intervention markedly reduced ptau protein levels and upregulated IR and IRS-1 in the rat brain (Akhtar et al., 2020). Taken together, activation of the PI3K/Akt/GSK-3β pathway may alleviate Aβ deposition by reversing insulin resistance.

ERK/JNK/p38 MAPK signaling pathway
Mitogen-activated protein kinases (MAPK) include extracellular regulated protein kinases (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK (Chang et al., 2018). The ERK/JNK/p38 MAPK signaling pathway (Fig. 2B) has been extensively investigated in the pathogenesis of AD. Activation of the MAPK signaling pathway in the brains of AD mice led to a significant increase in the levels of Aβ1-40 and Aβ1-42 (Zhao et al., 2005). Furthermore, hippocampal ERK1/2 activation has been demonstrated in the rat model of AD, and administration of an ERK inhibitor decreased the levels of phosphorylated tau protein in the brain tissues (Chong et al., 2006). In addition, studies on transgenic mice with AD have shown that the JNK pathway is activated in the brains, which correlates to significant tau protein phosphorylation and massive deposition of Aβ (Savage et al., 2002). Consistent with this, pharmacological inhibition of JNK markedly enhanced the cognitive performance in a rat model of AD injected intracerebrally with Aβ (Ramin et al., 2011). In addition, clinical studies show overexpression of p38 in the hippocampal and cortical neurons, and colocalization of p38 with tau protein in the brains of AD patients (Zhu et al., 2000).
In one study, mice were injected with Aβ1-42 into the right hippocampus to induce AD (Chang et al., 2018), and the animals were respectively treated with specific inhibitors of ERK, JNK and p38. While the JNK and p38 inhibitors increased the expression of the IDE protein in the cortex and hippocampus, whereas ERK inhibition reduced IDE levels. Overall, there was a significant decrease in the amount of accumulated Aβ, which coincided with improvements in cognitive function. In another study, administration of the cocaine and amphetamine-regulated transcript (CART) peptide in the APP transgenic mice downregulated phosphorylated ERK (p-ERK), phosphorylated JNK (p-JNK), and phosphorylated p38 (p-p38) in the hippocampus, promoted IDE mRNA expression and reduced Aβ protein levels, leading to significant improvement in cognitive function (Yin et al., 2017). Thus, we can surmise that inhibition of the ERK/JNK/p38 MAPK signaling pathway in the CNS can enhance Aβ degradation and alleviate cognitive impairment in AD models.
However, in both of these studies, Chang et al. showed that ERK suppression in the brains of the AD mice reduced the expression of IDE Table 4 The probable role of IDE in improving AD (transgenic mice). Abbreviations: Aβ, amyloid-β; AD, Alzheimer's disease; APP, amyloid precursor protein; GFAP, glial fibrillary acidic protein; Iba1, ionized calcium binding adapter molecule 1; IDE, insulin-degrading enzyme; IL-1β, interleukin 1β; IL-6, interleukin 6; NF-κB, nuclear factor kappa-B; NGF, nerve growth factor; p-tau, phosphorylated tau; TNF-α, tumor necrosis factor-α. (Chang et al., 2018). In contrast, Yin et al. found that inhibiting ERK phosphorylation increased IDE expression (Yin et al., 2017). This difference can be attributed to the different mouse strains and modeling strategies (C57BL/6 and APP transgenic) used in the two studies. In addition, while Chang et al. used ERK inhibitors directly and measured total IDE protein levels, Yin et al. administered CART peptide and mainly analyzed IDE mRNA expression. Nevertheless, it may be possible to regulate the expression of IDE in the brain by targeting the ERK/JNK/p38 MAPK pathway. However, the optimal inhibitor and dosage need to be ascertained, and future studies will have to address the selection of the AD model.

PPAR-γ signaling pathway
Peroxisome proliferator-activated receptor-γ (PPAR-γ), a nuclear hormone receptor of the PPAR subfamily, can bind to the peroxisome proliferator response element (PPRE) and regulate the expression of IDE (Du et al., 2009;Schoonjans et al., 1996). Thus, activating PPAR-γ can improve the cognitive impairment associated with AD or diabetes via the upregulation of IDE and clearance of Aβ (Du et al., 2009). The schematic illustration of PPAR-γ signaling pathway is shown in Fig. 2C. Quan et al. induced an in vitro model of AD by treating neuronal cells with Aβ1-42, and found that pioglitazone and ginsenoside Rg1 could activate PPAR-γ, upregulate IDE levels and reduce accumulation of Aβ (Quan et al., 2020;Quan et al., 2019). APP transgenic mice treated with GFT1803, a novel PPAR-γ agonist, showed significant improvement in cognitive function (Kummer et al., 2015), which could be attributed to increased IDE expression in the brain tissues and decreasing Aβ deposition in the cerebral cortex and hippocampus. Likewise, notoginsenoside R1 (NTR1) significantly enhanced IDE expression in the cerebral cortical tissue of APP transgenic mice and decreased Aβ levels in the cortex and hippocampus, as well as deposition of Aβ plaques in the brain. In addition, NTR1 intervention significantly increased the expression of IDE and PPAR-γ in the N 2 a-APP695sw cells, and these effects of NTR1 were reversed by a PPAR-γ antagonist GW9662 . These findings indicated that the regulatory effect of NTR1 on IDE is likely mediated through the PPAR-γ pathway.
According to the aforementioned studies, the onset of AD is accompanied by hyperphosphorylation and downregulation of PPAR-γ in the CNS, which leads to a significant decrease in the expression of IDE and enhanced Aβ deposition. PPAR-γ agonists upregulated PPAR-γ by inhibiting phosphorylation, thereby promoting IDE expression and reducing Aβ deposition. Therefore, the PPAR-γ pathway is critical to the pathophysiological process of AD, and its activation can slow disease progression and ameliorate cognitive decline.

NF-κB signaling pathway
NF-κB, a heterodimer composed of the subunits p50 and p65, and plays a key role in the inflammatory response (Beg et al., 1992). One clinical study showed that individuals with AD express high levels of NF-κB in the neurons (Boissiere et al., 1997). In addition, high NF-κB p65 expression in the hippocampus, temporal and frontal areas of the brain in AD patients correlate with massive Aβ deposition, indicating a close relationship between Aβ deposition and NF-κB activation (Liao et al., 2016). Activation of the NF-κB signaling pathway promotes the formation of amyloid plaques and is therefore a key driver of neuronal degeneration (Granic et al., 2009;Zuo et al., 2015). Therefore, the NF-κB signaling pathway (Fig. 2D) is a promising therapeutic target for AD.
Thymosin β4 (Tβ4) intervention in APP transgenic mice significantly reduced the phosphorylation of NF-κB and inhibited downstream activity in the cerebral cortex and hippocampus, which led to a significant increase in IDE expression and reduce Aβ deposition in these tissues, eventually improving cognitive impairment . In another study (Lin et al., 2014), a mouse model of cognitive impairment was established by injecting male Kunming mice intraperitoneally with 150 mg/kg of D-galactose (D-gal), and the cognitive decline was confirmed by the Morris water maze test. Administration of madecassoside significantly reduced the expression of NF-κB p65 and phosphorylated NF-κB p65 (p-NF-κB p65) in the hippocampus, resulting in elevated IDE and reduced levels of APP and Aβ1-42, and better cognitive performance.
To summarize, pharmacological interventions that inhibit NF-κB hyperphosphorylation can mitigate AD-related cognitive impairment by promoting IDE expression and Aβ degradation in the CNS.

AMPK signaling pathway
AMP-activated protein kinase (AMPK) is involved in protein synthesis and glucose metabolism, and exerts anti-inflammatory and antioxidant effects (Hardie, 2008). The anti-inflammatory effect of AMPK is mediated via the inhibition of NF-κB (Jeon, 2016). Studies show that activating AMPK in the CNS can lessen tau protein hyperphosphorylation and alleviate AD-related cognitive impairment by inhibiting GSK3β (Kim et al., 2015). In addition, pharmacological activation of AMPK-related pathways in AD mice reduced Aβ deposition in the brain and improved cognitive function (Corpas et al., 2019;Gong et al., 2019). Therefore, it is possible that the AMPK pathway (Fig. 2E) also mediates IDE-dependent degradation of Aβ.
Simvastatin treatment significantly increased the levels of phosphorylated AMPK (p-AMPK) and activated the AMPK pathway in primary cultured astrocytes. The stimulated cells secreted high levels of IDE in a time-and dose-dependent manner, resulting in a significant decrease in intracellular Aβ (Lu et al., 2020). Furthermore, metformin intervention in APP transgenic mice significantly improved cognitive function by upregulating p-AMPK and IDE, and decreasing the expression of Aβ1-40 and Aβ1-42 (Son et al., 2015).
To summarize, the PI3K/Akt/GSK3β, ERK/JNK/p38 MAPK, PPAR-γ, NF-κB and AMPK signaling pathways mediate IDE-dependent cognitive improvement in models of AD (Table 5 and Fig. 3). And the potential mechanisms by which these pathways alleviate the symptoms of cognitive impairment in AD focus on promoting the expression of IDE in the CNS for the effect of degrading Aβ and decreasing the expression or accumulation of Aβ in the brain.

PI3K/Akt/GSK-3β signaling pathway
Given its role in insulin resistance, the PI3K/AKT/GSK-3β signaling pathway has also been studied extensively in diabetes-related cognitive impairment.
STZ-induced diabetic mice showed severe cognitive deterioration according to the Barnes Circular Maze Task nine weeks after successful modeling. Furthermore, phosphorylated insulin receptor (p-IR), p-Akt and p-GSK-3β expression were significantly decreased in these mice, which resulted in central insulin resistance and inhibited IDE expression in the brain, leading to Aβ and p-tau accumulation and cognitive impairment (Jolivalt et al., 2008). Furthermore, a rat model of HFD-induced insulin resistance showed significantly lower insulin levels in the cerebrospinal fluid compared to that in the control mice, indicating that insulin signaling in the brain was impaired in the former. Administration of pioglitazone to the insulin-resistant rats significantly increased IDE protein and mRNA levels, decreased the expression of APP and Aβ, and upregulated Akt and GSK-3β in the rat brain (Yang et al., 2017). Likewise, gavage of alpha-lipoic acid (ALA) in HFD-fed and  (Son et al., 2015) Abbreviations: Aβ, amyloid-β; AD, Alzheimer's disease; Akt, protein kinase B; AMPK, AMP-activated protein kinase; APP, amyloid precursor protein; D-gal, Dgalactose; ERK, extracellular regulated protein kinases; GSK-3β, glycogen synthase kinase-3β; ICV, intracerebroventricular; IDE, insulin-degrading enzyme; IR, insulin receptor; IRS-1, insulin receptor substrate 1; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinases; NF-κB, nuclear factor kappa-B; PI3K, phosphoinositide 3-kinase, PPAR-γ, peroxisome proliferator-activated receptor-γ; p-tau, phosphorylated tau; SD, Sprague Dawley; STZ, streptozotocin.
STZ-induced diabetic mice significantly alleviated hyperinsulinemia by upregulating PI3K, p-Akt, p-GSK-3β and IDE in the brain, which alleviated the symptoms of cognitive impairment (Ko et al., 2021).

Cdk5/p35 signaling pathway
Cyclin-dependent kinase 5 (Cdk5), a member of the cyclindependent kinases family, is mainly expressed in the post-mitotic neurons, and its activation is dependent on p35 (Dhariwala, Rajadhyaksha, 2008). Oxidative stress, inflammatory response and Aβ deposition can trigger overactivation of Cdk5 in the CNS, leading to a series of neurotoxic responses that culminate in neuronal apoptosis (Lopes, Agostinho, 2011). Previous studies have demonstrated aberrant activation of Cdk5 in diabetic mice, which is associated with severe neuronal apoptosis and cognitive impairment, which were alleviated by inhibition of Cdk5 . The schematic illustration of Cdk5/p35 signaling pathway is shown in Fig. 4A.
In the STZ-induced diabetic mouse model, the ginsenoside Rb1 significantly reduced impaired glucose tolerance in the glucose tolerance test (GTT) and insulin resistance in the insulin tolerance test (ITT) in the peripheral system. In addition, in the CNS, Cdk5/p35 activity was reduced significantly in the hippocampus following treatment, which increased IDE expression and improved the cognitive performance of mice. Thus, inhibiting Cdk5/p35 activity in the CNS may have a beneficial effect on diabetes-induced cognitive impairment (Yang et al., 2020b).

cAMP/PKA signaling pathway
Cyclic adenosine monophosphate (cAMP) is an intracellular second messenger regulated by hormones, neurotransmitters and G proteincoupled receptors (GPCRs), and cAMP-dependent protein kinase A (PKA) is a serine/threonine kinase (Yang, Yang, 2016). The cAMP/PKA signaling pathway regulates insulin and glucagon activity and glucose homeostasis (Yang, Yang, 2016). Excessive Aβ deposition in the brain may compromise this pathway and induce neuronal damage, thereby exacerbating cognitive impairment (Tong et al., 2001). The schematic illustration of cAMP/PKA signaling pathway is shown in Fig. 4B.
APP transgenic mice injected intraperitoneally with STZ exhibited hyperglycemia symptoms as well as cognitive impairment. The cAMP agonist Bucladesine significantly reduced IDE activity and expression in a dose-dependent manner, whereas the PKA inhibitor H-89 had opposite effects. Activation of the cAMP/PKA signaling pathway may prevent IDE expression in the brain during the pathogenesis of diabetes-related cognitive impairment. Conversely, inhibiting this pathway can prevent cognitive deterioration by promoting IDE expression and reducing neuronal apoptosis (Li et al., 2018).
To summarize, the PI3K/Akt/GSK3β, Cdk5/p35 and cAMP/PKA signaling pathways can alleviate diabetes-related cognitive impairment (Table 6 and Fig. 5) by increasing IDE expression in the CNS, decreasing insulin resistance in the peripheral system, and reducing neuronal apoptosis in the brain.
The PI3K/Akt/GSK-3β signaling pathway is involved in both AD and diabetes-related cognitive impairment. Activation of this pathway can alleviate AD-related cognitive impairment by increasing IDE expression in the brain and reducing Aβ accumulation. On the other hand, the improvement of diabetic cognitive impairment also involves reduction in neuronal apoptosis and improved peripheral insulin resistance and glucose tolerance. The relevant signaling pathways summarized in this review warrant further investigation for a deeper understanding of the mechanisms involved in cognitive impairment.

Conclusion and future prospects
Both AD and diabetes-related cognitive impairment involve deposition of Aβ in the brain, prompting researchers to consider AD as "type 3 diabetes". In addition, IDE activity is also impaired in diabetes and AD (Pivovarova et al., 2016), and may play a critical role in their onset (Akhtar et al., 2016;Sousa et al., 2021). Since IDE can degrade both insulin and Aβ, it may be instrumental in mitigating the cognitive impairment caused by diabetes and AD through multiple pathways. In most studies conducted so far, the role of peripheral IDE activity or the alleviation of diabetic symptoms in the context of cognitive impairment has not been addressed sufficiently and will have to be the focus of future studies. In addition, the specific mechanisms of IDE regulation in the CNS and peripheral systems (e.g., liver tissue) during the onset of diabetes, and the effect on insulin and blood glucose changes, also need to be elucidated.
Although the dual function of IDE in degrading both Aβ and insulin presents some therapeutic prospects for diabetes and AD, there are some inconsistencies. For instance, Aβ and insulin compete for IDE, and IDE preferentially degrades insulin in diabetic patients with hyperinsulinemia (Qiu, Folstein, 2006). This can be attributed to the stronger affinity of IDE for insulin. Incomplete degradation of Aβ and insulin can cause hyperinsulinemia and massive Aβ deposition in diabetic patients, which aggravate insulin resistance and diabetes-related cognitive impairment. Therefore, the therapeutic use of IDE against diabetes-related cognitive impairment should take into consideration the following: 1) the expression and distribution of IDE across different brain regions and types of cells to determine the sites of effective Aβ degradation, 2) the expression of IDE in the peripheral system and its impact on insulin degradation, insulin resistance and hyperinsulinemia, and 3) the identification of pathways connecting IDE, insulin, glucose and Aβ in the central and peripheral systems.
In conclusion, IDE-mediated degradation of insulin and Aβ is a promising target for mitigating the symptoms of cognitive impairment associated with AD as well as diabetes.

CRediT authorship contribution statement
Yue Tian: Writing-Original draft preparation, Writing-Reviewing and Editing. Guangchan Jing: Editing. Mengren Zhang: Conceptualization, Supervision. All authors have read and approved the final manuscript.

Data Availability
Data will be made available on request.