Increased Brain Insulin Resistance Associated with Cognitive Decline in Alzheimer’s Disease Subjects

ABSTRACT

Alzheimer’s Disease (AD) is a neurodegenerative disorder which slowly deteriorates neurons and impairs connections involved in memory and thinking. The discovery of insulin receptors in the brain led to the notion that the brain is insulin sensitive and recent research has shown a connection between a decrease in brain insulin sensitivity (or brain insulin resistance) and cognitive deterioration in AD patients. AD symptoms of cognitive dysfunction are seen through the expression of amyloid pathology– a symptom that appears to be driven by insulin resistance within the brain–but can be reversed through intranasal therapeutics. Additionally, the changes in protein expression after intranasal delivery of insulin/analogue can help determine the mechanistic pathway of insulin sensitivity. We reviewed studies that analyzed possibly dysregulated proteins within the insulin signaling pathway and volumes of insulin-sensitive regions of the brain. We also viewed studies that observed the physical changes in memory as well as cellular changes in mRNA expression of insulin signaling pathway proteins IRS-1, Akt, GSK-3𝛼, and GSK-3ß after administration of intranasal insulin/analogue in AD mice. Insulin resistance occurs coincidently with amyloid pathology: as levels of insulin signaling pathway proteins IRS-1, Akt, and GSK-3ß were found to be dysregulated, and brain volumes of insulin-sensitive areas within the cerebral cortex were found reduced, exacerbating AD cognitive deficits. However, those AD deficits were reversed through intranasal insulin/analogue delivery. The studies reviewed in this paper elucidate the notion that insulin resistance is clearly linked to AD as results showed dysregulation within insulin signaling and the cause of brain volume depletion within key brain regions sensitive to insulin. 

INTRODUCTION

In the 1970s, the discovery of an abundance of insulin receptors in the brain eventually led to the understanding that insulin, in addition to its metabolic effects, played a central role to the neuronal connections in the brain (Hopkins and Williams 1997). Brain insulin sensitivity measures how neuronal cells respond to insulin, which result in cellular actions such as cell growth and repair, sugar metabolism, and even gene expression. Researchers have noticed a connection between brain insulin resistance in Alzheimer’s Disease (AD) patients resulting in neurodegenerative symptoms such as significant decline in a person’s memory and cognitive ability (Velazquez et al. 2017). However, recent studies utilizing intranasal drug administration have demonstrated a reversal of this cognitive dysfunction using various rodent models (Rajasekar et al. 2017; Kazkayasi et al. 2022).

Although an abundance of literature supports the notion of the association between brain insulin resistance and cognitive impairment, many questions are left unanswered regarding the role of the specific proteins in the signaling pathway and how intranasal therapeutics help enhance memory function. For example, there is a lack of research on how the nonfunctional IR affects memory and, with intranasal therapeutics, it is unclear whether the therapy restores the insulin signaling pathway or simply assists the movement of insulin past the blood brain barrier. There is also a possibility that many different pathways and factors, in conjunction, could result in brain insulin resistance and AD neurodegenerative symptoms.

Here we review the current literature that illustrates evidence of the causative relationship insulin resistance has to AD. Animal and human models have strengthened the validity of this linkage: rodent models are used to closely monitor insulin signaling pathways while studies of humans highlight key insulin-sensitive brain regions. We also view studies that utilize intranasal therapeutics on rodent models to demonstrate the clear effects of how AD mice improve cognitive function after administration of intranasal therapies. Lastly, we utilize the intranasal studies to surmise potential targets in the signaling pathway that could be affecting neural connections due to defective insulin signaling.

BACKGROUND

Insulin is a peptide hormone secreted by pancreatic beta cells and serves several vital roles within the body, including energy storage and glucose metabolism. Insulin resistance is caused by chronically elevated insulin levels which leads to disrupted signaling between insulin and insulin receptors, in turn making the body less sensitive to insulin signaling. Brain insulin signaling plays a role in maintaining neurons and synapses, making it a key player in learning and memory function (Velazquez et al. 2017).

Insulin signaling also plays a role in regulating protein synthesis and degradation. One of the proteins this affects is the amyloid-beta protein. In cases of disrupted insulin signaling, there is less clearance of amyloid-beta protein and its accumulation can cause the formation of amyloid-beta (Aβ) plaques (James et al. 2017). These plaques tend to be located between neurons, deteriorating their function and synapses. The protein amyloid-beta is found at abnormally high levels in AD brains due to elevated insulin dysregulation. Subsequently, increased Aβ plaques are present as part of AD pathology and have been found to directly diminish memory function (Smith et al. 2013). 

These plaques specifically can further disrupt the insulin signaling pathway by decreasing expression of the insulin receptor (Wei et al. 2021). For reference, the signaling pathway for insulin consists of insulin receptors, located on the nerve cells in the brain. Eventually, insulin docks onto the insulin receptor (IR) leading to dimerization and phosphorylation. Ultimately, activation of downstream signaling allows for glucose uptake into the brain cell which proves important for cognitive learning and retaining memory (Kazkayasi et al. 2022). IRS-1, Akt, GSK-3𝛼, and GSK-3ß are all also important in the pathway as these downstream signaling proteins, once activated via phosphorylation, amplify the signal and allow the cell to produce necessary components to aid in the uptake of glucose. 

BRAIN INSULIN RESISTANCE AND INTRANASAL THERAPEUTICS

Insulin Resistance is Linked to Alzheimer’s Disease Through the Development of Cognitive Dysfunction 

The desensitization of insulin receptor signaling is theorized to be mechanistically influential in the progression of AD, specifically with worsening cognitive decline (Velazquez et al. 2017). The tie between AD pathology and insulin resistance is modeled in studies of AD brains of both animals and humans. Velazquez et al. (2017) utilized mice models to investigate insulin resistance and sensitivity associated with AD. Three different mice models were used. Tg2576 and 3xTG-AD mice demonstrated AD-like pathology while wildtype (WT) mice were used as a control group for comparison. Tg2576/3xTG-AD mice are differentiated by their Aβ plaque forming tendencies. Tg2576 mice exhibit a late plaque model as they carry the amyloid precursor protein (APP) gene which produces initially slow, but progressively accelerated plaque formation with increasing age. Whereas, 3xTG-AD mice exhibit an early plaque model as they carry both APP and an additional amyloid precursor protein Presenilin-1 (PS1) gene which produce an initial abrupt and accelerated plaque formation pattern (Lee and Han 2013).

To assess insulin resistance, the Velazques et al, (2017) study measured phosphorylation levels of insulin pathway proteins from hippocampal tissue. Levels were determined through viewing band intensities of Western blots. Hippocampal tissue in particular was chosen because all groups of mice used in this experiment present hippocampal-dependent learning and memory ability. The proteins measured include insulin receptor substrate-1 (IRS-1), alpha kinase protein (Akt), and glycogen synthase kinase-3 beta (GSK-3ß). The possibility these proteins have to compromise insulin signaling as previously mentioned makes them adequate indicators of insulin resistance. Figures 1, 2, and 3 contain results of these Western blots. Analyzing these results show a pattern of pathway protein levels changing with age in AD modeled mice while staying consistent in WT mice. This indicates that brain insulin resistance, apparent by dysregulated pathway proteins, is specific to AD. 

To continue studies on the relationship between insulin resistance and AD, Lee J. et al. (2018) examines AD in human models. In this study, 160 human participants aged 65 years and up were chosen from a dementia clinic. Table 1 provides further demographic and assessment data on these participants. Magnetic resonance imaging (MRI) was carried out on all participants to visualize the brain and glucose-stimulated insulin secretion levels (Lee, J. et al. 2018). Several assessment tools were then used to analyze these images. To assess cognitive function, the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) was used, which provides a prediction in cognition differences between normal aging versus AD. Scores range from 0 to 100, with lower scores correlating to more severe cognitive impairment. Scoring is based on performance on tests regarding naming, memory, recall, and recognition of word lists, spatial patterns, and verbal fluency abilities. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was also used to assess the extent of insulin resistance by calculating an index of plasma glucose to plasma insulin levels. Multivariate Analysis of Covariance (MANCOVA) was then used to figure out which key brain regions to focus on based on sensitivity to insulin. MarsBaR and Automated Anatomical Labeling were additionally used to obtain volume measurements within these brain regions determined from the MRI’s. Finally, a Hierarchical Moderated Multiple Regression (MMR) model was used to analyze the relationship between insulin resistance, brain volumes, and cognitive function (Lee, J. et al. 2018).

These methods tested 14 regions within the cerebral cortex, which is the outer layer of the brain and has distinct lobes. Table 2 shows results of all regions measured. The most significant results were notable volume reductions of the right orbitofrontal gyrus, right middle cingulate gyrus, right hippocampus, and right precuneus. The right orbitofrontal gyrus and right middle cingulate gyrus are within the frontal lobe of the cerebral cortex. Damage to the frontal lobe can cause memory, attention, emotional, social behavior, and speech issues. Additionally, the right hippocampus is located within the temporal lobe which can lead to hearing and memory issues, difficulty in understanding language, and inability to identify faces or objects if damaged. Lastly, the right precuneus is located within the parietal lobe, damage of which can cause symptoms such as challenges with critical thinking, lack of hand to eye coordination, and problems with memory retrieval (Venkat 2022). These discovered volume reductions serve as pathological brain damage which directly leads to cognitive impairment due to their important roles within the brain (Lee, J. et al. 2018). 

Together these studies show the substantial effect insulin signaling has in the brain. Findings of insulin dysregulation through samples of insulin signaling protein within the hippocampal tissue of the AD mice model brains in the Velazquez et al. (2017) study supports the evidence of insulin resistance specifically affecting the brain. Furthermore as the Lee, J. et al. (2018) study discusses, insulin dysfunction has a negative effect on neural processes, rendering neurons more vulnerable to metabolic stresses, and a consequent decrease in brain volume. This reduction in volume is significant because it also causes a reduction in cognitive ability. The correlation of insulin resistance interplaying with the manifestation of Aβ plaques in AD pathology serves as a specific source to what exactly causes the brain volume reduction associated with AD. In all, the insulin resistance that occurs with AD perpetuates this insistent cycle of cognitive decline. Since this connection has been discovered, insulin has been a key focus of study for possible AD treatments. 

Intranasal Therapeutics for Signal Pathway Discovery & Cognitive Improvement

        The blood-brain barrier (BBB) consists of tight junctions of endothelial cells which tightly regulate what components move to and from the blood and into the brain. The tight junctions limit the passage of large ions, proteins, and molecules while only small molecules are freely permissible to reach the central nervous system (CNS). Due to this strict regulation, treating neurodegenerative diseases–such as Alzheimer’s or Parkinson’s Disease (PD)–become difficult as the BBB prevents the passage of drugs or hormones from reaching the CNS. In 1989, William Frey II proposed intranasal therapeutics as a method to bypass the BBB. His intranasal delivery technique has led to a vast amount of literature and research we see today surrounding prospective neurodegenerative treatments (Crowe et al. 2018). Specifically, studies from the 2000s–focused mainly on intranasal insulin delivery as a treatment for AD– noticed results of insulin improving “attention, memory, and cognitive function” among AD and PD mice models (Crowe et al. 2018).

Through the specific studies we viewed, intranasal therapeutics proved as useful treatments in improving cognitive function in AD induced rodent models. These studies were also used as a means to discover which proteins from the insulin signaling pathway are upregulated and downregulated before and after administration of intranasal insulin (Rajaesekar et al. 2017; Kazkayasi et al. 2022). And, by determining the changes in expression, advancements can be made in identifying the specific insulin signaling pathway that is used by neuronal cells. 

Intranasal Therapeutics Reverses Memory Loss in Induced Alzheimer’s Disease Rodent Models

        Rajasekar et al. (2017) measures the effects of intranasal insulin on adult male rats that had induced AD. Intracerebroventricular streptozotocin (ICV-STZ) was used to induce cognitive decline and mimic symptoms of AD. In total, there were four groups of treatments administered to rats: group 1 control (received artificial cerebrospinal fluid (aCSF) and intranasal saline); group 2 received intracerebroventricular streptozotocin (ICV-STZ) and intranasal saline; group 3 received ICV-STZ and intranasal insulin; and group 4 received aCSF with intranasal insulin (labeled control, ICV-STZ, STZ+INS, and Per se INS respectively) (Rajasekar et al. 2017). After the treatments were administered, Morris Water Maze (MWM) testing, which is a swimming test evaluating spatial memory and learning, was completed to measure changes in cognitive function in rats. Additionally, mRNA expression of IR and various other proteins known to be part of the insulin signaling pathway was measured (Rajasekar et al. 2017).

Rats receiving STZ +INS performed significantly better than the group only receiving the ICV-STZ treatment [Fig. 4a-b]. Moreover, rats receiving INS after STZ administration had shorter latency times and path lengths after each MWM session, illustrating cognitive improvement after insulin treatment (Rajasekar et al. 2017). As seen in Figure 4c,  the respective path length to the platform for the STZ+INS mimics the path for the control group in the MWM, further demonstrating that insulin therapies aid in cognitive function (Rajasekar et al. 2017). However, the group receiving the artificial CSF with intranasal insulin did not have significantly greater cognitive improvement in comparison to the control group, indicating that there may be a limit to how impactful intranasal insulin administration could be for neuronal activity (Rajasekar et al. 2017).

Another study, performed by Kazkayasi et al. (2022), viewed the effects of intranasal metformin in mice induced with memory loss by ICV-STZ. Metformin is an antidiabetic agent prescribed to Type-2 diabetes patients and mimics the effects of insulin by regulating or lowering blood glucose levels in the body. If metformin is an analogue drug to insulin, it would be hypothesized that the results of the study performed by Kazkayasi et al. (2022) would be similar in nature to intranasal insulin administration studies performed by Rajasekar et al. (2017). The metformin study had four experimental groups of mice: control receiving aCSF, AD mice receiving the ICV-STZ, mice receiving metformin orally after ICV-STZ, and mice receiving metformin intranasally after ICV-STZ (referred to as control, AD, intranasal, and oral respectively). Similar to the prior study, Kazkayasi et al. (2017) also utilized the MWM method to test for memory improvement and spatial learning in mice after the administered treatments. The results of this study found that intranasal administration of metformin given to mice after ICV-STZ treatment (intranasal group) displayed increased spatial learning and memory improvement through the shorter latency times, which was depicted through the shorter travel distance in finding the platform in the MWM test after each subsequent session [Fig. 5c] (Kazkayasi et al. 2022). 

The cumulative data illustrates that intranasal therapeutics restores cognitive decline in mice induced with AD. Additionally, the two studies arrive at similar results, indicating that an analogue of insulin also is sufficient in achieving the same effects of intranasal insulin in AD induced mice. With further research, these therapies could potentially be beneficial in ameliorating cognitive impairment and neurodegeneration seen in Alzheimer’s Disease patients.

Intranasal Therapies Utilized to Determine Signaling Pathway in Insulin Signaling Resistance

In addition to examining spatial learning and memory, Rajasekar et al. (2017) viewed the level of mRNA expression of IR and other proteins in the cerebral cortex and hippocampus of the four experimental groups of rats. The study conducted Western blots on tissue extracts of the cerebral cortex and hippocampus and used densitometric quantification of the bands (Rajasekar et al. 2017). The ICV-STZ group had downregulation of IR mRNA expression in comparison to the control; whereas, the STZ+INS group had an upregulation of the IR mRNA expression in comparison to the control (Rajasekar et al. 2017). Therefore, it can be inferred from the data from figure 6 that there is an association between a decrease or lack of insulin receptors and cognitive decline, proving that IR are an essential aspect of the insulin signaling pathway in the brain. Additionally, cognitive impairment seen in AD potentially correlates to the downregulation of IR. However, there was not a significant increase in IR expression with the Per se INS group (received aCSF with intranasal insulin), indicating that intranasal insulin would not prove as a beneficial therapy without significant levels of neuronal deterioration (Rajasekar et al. 2017).

Moreover, further downstream proteins from IR that are essential for insulin signaling are upregulated in the STZ+INS group when viewing the relative mRNA expression (Rajasekar et al. 2017). Figure 6b-e corroborates the upregulation of insulin receptor substrate-1 (IRS-1), alpha protein kinase (Akt), glycogen synthase kinase 3 alpha (GSK-3𝛼), and glycogen synthase kinase 3 beta (GSK-3ß) in the STZ+INS group of rats while a downregulation of all four proteins in ICV-STZ administered rats (Rajasekar et al. 2017). 

Kazkayasi et al. (2022) also utilizes intranasal metformin to demonstrate the upregulation or downregulation of insulin signaling proteins on ICV-STZ treated mice. Specifically, the study investigated how ICV-STZ induced mice compare with ICV-STZ mice treated with intranasal metformin with expression of phosphorylated IR and Akt. Western blotting was done on homogenized hippocampal/cerebral brain tissues, and liquid chromatography and mass spectroscopy were used to quantify the levels of metformin in the hippocampal and cerebral tissues (Kazkayasi et al. 2022). Figure 7 and figure 8 illustrate that ICV-STZ induced mice compared to intranasal metformin treated mice had no effect on the expression of insulin receptors in the hippocampus and cerebral cortices; however, there was an increase in expression of the phosphorylated IR (Kazkayasi et al. 2022). Similarly, there was no significant difference between ICV-STZ induced mice and intranasal metformin treated mice for Akt expression, but intranasal metformin mice had increased expression of phosphorylated Akt in both the hippocampus and cerebral cortices.

Both studies finding the downregulation and/or upregulation of insulin signaling proteins  suggested that specific aspects of the insulin signaling pathway are affected and result in neurodegeneration or neurogenesis. Rajasekar et al. 2017 saw the upregulation of IR, IRS-1, Akt, GSK-3𝛼, and GSK-3ß after intranasal insulin administration in AD induced rats. Kazkayasi et al. 2022 viewed the upregulation of IR-phosphorylated and Akt-phosphorylated in the intranasal metformin treatment in AD induced mice. Thus, it can be inferred that, along with the insulin receptor, the downstream proteins are also integral in proper insulin signaling in the brain leading to increased brain insulin sensitivity. And, non-functioning insulin receptors and/or downstream proteins eventually lead to neurodegeneration or cognitive decline. Lastly, Kazkayasi et al. 2022 viewed no difference in IR and Akt expression contradicting the results of increased IR and Akt expression in the study conducted by Rajasekar et al. (2017). While the reasoning behind conflicting results is not known, it can be surmised that phosphorylation plays a significant role in activating proteins which could amplify the downstream signaling effects of the insulin signaling cascade in the brain. This could be a reason as to why a greater difference in upregulation was seen when phosphorylation was involved in the Kazkayasi et al. (2022) study. 

CONCLUSION

Much of the current evidence regarding brain insulin sensitivity in neurodegenerative diseases, such as Alzheimer’s, point to the failure of insulin transport and defective insulin signaling pathways as a cause of memory impairment and cognitive dysfunction. Supporting this evidence, aforementioned Tg2576/3xTg-AD mice models showed that insulin signaling dysfunction is more apparent in AD mice than WT mice (Velazquez, et al. 2017). This was determined by an observed age-dependent change in insulin signaling pathway protein (IRS-1, Akt, GSK-3ß) levels. Human AD brain models additionally pointed out key insulin-sensitive brain regions including the orbitofrontal gyrus, cingulate gyrus, hippocampus, and precuneus. Since these regions interact more heavily with insulin, they experience a decrease in volume from dysfunctional AD insulin signaling, resulting in cognitive decline (Lee, J. et al. 2018). The work done by Velazquez et al. (2017) and Lee, J. et al. (2018) suggests that finding ways to reduce insulin signaling dysfunction in patients with AD may help reduce insulin resistance and possibly improve cognitive effects. On this account, intranasal therapeutic studies illustrate the improvement of memory loss in rodent models after administering insulin or an analogue drug (Rajasekar et al. 2017; Kazkayasi et al. 2022). Further evidence from these studies indicates that after administration of intranasal insulin/analogue, there is an upregulation of insulin receptor and downstream signaling proteins (IRS-1, Akt, GSK-3𝛼, GSK-3ß), indicating specific insulin signaling targets (separately or in conjunction) may be the cause of memory loss seen in AD subjects (Rajasekar et al. 2017). As stated before, it is not exactly known whether intranasal insulin/insulin analogue administration affects the insulin signaling pathway or aids insulin transport past the blood brain barrier; so, further work is needed to understand the specific cellular mechanism. Thus greater research and understanding of known existing insulin signaling pathways and proteins could possibly give further insight to differences and similarities to brain insulin signaling. And lastly, further studies must be conducted on intranasal therapies to ensure the benefits outweigh the costs or risks before they are applied to human models. Progress on making therapeutics available to the public is worthy of great attention to improve the lives of all those affected by AD. 

TABLES & FIGURES

Table 1.  Study Population 

Table 2. Brain Matter Reduction from Insulin Resistance 

Figure 1. Total and Phosphorylated IRS-1 Levels in the Brains of Tg2576, 3xTg-AD, and WT mice. 

Figure 2. Total and Phosphorylated Akt Levels in the Brains of Tg2576, 3xTg-AD, and WT mice. 

Figure 3. Total and Phosphorylated GSK-3ß Levels in the Brains of Tg2576, 3xTg-AD, and WT mice. 

Figure 4. Rats receiving intranasal insulin treatments ameliorated cognitive impairment. 

Figure 5. Swim speed and path track were measured with the Morris Water Maze test in the mice groups receiving the four experimental treatments.

Figure 6. Insulin receptor and downstream insulin signaling protein upregulation seen in the cerebral cortex and hippocampus of rats treated with intranasal insulin.

Figure 7. Mice given intranasal metformin resulted in elevated phosphorylated IR and phosphorylated AKT in the hippocampus of the brain.*

Figure 8. Mice given intranasal metformin increases expression of phosphorylated IR and phosphorylated AKT in the cerebral cortex of the brain.

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