The Metabolic Basis for Nervous System Dysfunction in Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease

Abstract

Disorders of metabolism affect multiple systems throughout the body, but may have the greatest impact on both central and peripheral nervous systems. Current available treatments and behavior changes for disorders that include diabetes mellitus (DM) and nervous system diseases are limited and cannot reverse disease burden. Greater access to healthcare and a longer lifespan has led to increased prevalence for metabolic and neurodegenerative disorders. In light of these challenges, innovative studies into the underlying disease pathways offer new treatment perspectives for Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease. Metabolic disorders are intimately tied to neurodegenerative diseases and can lead to debilitating outcomes, such as multi-nervous system disease, susceptibility to viral pathogens, and long-term cognitive disability. Novel strategies that can robustly address metabolic disease and neurodegenerative disorders involve a careful consideration on cellular metabolism, programmed cell death pathways, the mechanistic target of rapamycin (mTOR) and its associated pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), growth factor signaling, and underlying risk factors such as the apolipoprotein E (APOE-ε4) gene. Yet, these pathways are complex and necessitate comprehensive understanding to achieve clinical outcomes that target disease susceptibility, onset, and progression.

1. The Implications for Metabolic Dysfunction

Approximately 500 million individuals have metabolic disease and diabetes mellitus (DM) across the globe [1–3]. The costs for the treatment and care for patients with DM are are significant [4, 5]. At minimum, $20,000 United States Dollars (USD) per year are required to care for each individual with DM. Individuals with DM can experience costs for care that can now exceed $760 billion USD [6]. Care and treatment and for patients with DM requires greater than 17% of the Gross Domestic Product in the US per the Centers for Medicare and Medicaid Services (CMS) [7]. On top of these costs, another seventy billion USD are consumed for individuals with DM as a result of disability and functional loss. These financial concerns also impact different age groups of the population. Almost forty-five percent of the four million annual deaths that occur in individuals with DM affect those under the age of seventy [4]. In the United States (US), thirty-five million individuals, 10% of the population, can be given a diagnosis of DM [8, 9]. These numbers do not even consider that more than 400 million individuals can be at risk for developing DM or suffer from metabolic dysfunction [5, 6, 10, 11]. It is estimated that more than 7 million individuals 18 years of age or older are currently not recognized to have DM. As an example, approximately thirty-five percent of adults in the US are considered to have prediabetes as a result of their fasting glucose and hemoglobin A1c (HbA_1c) levels [12, 13].

Metabolic disease is increasing in prevalence more rapidly in low and middle income countries than in high income countries (Table 1). Approximately eighty percent of adults with DM are living in low- and middle-income countries [6]. DM prevalence has increased from nine and one-half percent during the period of 1999 to 2002 to twelve percent during the period of 2013 to 2016. Multiple factors can affect disease prevalence, such as education, co-morbidities, and socioeconomic status [13–15]. Approximately 13% of adults with less than a high school education have DM compared to 10% of individuals with a high school education and DM. If an individual has greater than a high school education, the risk decreases to seven and one-half percent. Other risk factors for leading to the progression of DM complications consist of hypertension, limited exercise, tobacco use, obesity, and elevated serum cholesterol [2, 3, 16–19]. When one considers obesity, increased body weight results in impaired glucose tolerance that that cause DM progression [20–26]. Obesity is an important factor that can raise the risk of developing DM in young individuals and can alter aging, inflammation, stem cell proliferation, oxidative stress exposure, and mitochondrial integrity [11, 27–33]. Increased weight and metabolic dysfunction also can affect underlying cellular pathways of the mechanistic target of rapamycin (mTOR) that translate to clinical disability with dementia and coronavirus disease 2019 (COVID-19) [3, 28, 34–37].

Table 1.

Highlights

At least 500 million individuals are believed to suffer from diabetes mellitus (DM) throughout the world, approximately seven million individuals over the age of 18 are undiagnosed with DM, and metabolic disorders significantly impact both the central nervous system and the peripheral nervous system. Neurodegenerative disorders, such as Alzheimer’s disease. Parkinson’s disease, and Huntington’s disease, affect more than one billion individuals throughout the world, include over six hundred disorders that lead to death and disability, and current treatment protocols and lifestyle modifications for metabolic and neurodegenerative disorders cannot reverse disease burden. Innovative strategies that can robustly target both metabolic disease and neurodegenerative disorders focus on metabolic homeostasis, programmed cell death pathways, the mechanistic target of rapamycin (mTOR) and its associated pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and underlying risk factors such as the apolipoprotein E (APOE-ε4) gene. Activation of mTOR signaling can be beneficial and lead to the prevention of ß-amyloid (Aβ) toxicity, increased vascular cell survival, and enhanced neuroplasticity. However, a fine balance in activation of these pathways is necessary since in other scenarios, induction of autophagy with decreased mTOR function may result in improved memory and more robust insulin signaling that can increase Aß clearance Current investigations must address not only disease progression, but also the risk of disease onset, since the ε4 allele of the apolipoprotein E (APOE-ε4) gene has been shown to affect mTOR signaling, increase mTOR activity, and alter autophagy flux that increases risk for the development of AD and also increases the susceptibility of viral infection during coronavirus disease 2019 (COVID-19) as well as promote long-term disability with dementia and long-COVID syndrome.

2. Metabolic Disease and Neurodegeneration

Non-communicable diseases (NCDs) include disorders of the nervous system [15, 38]. NCDs lead to at least 70% of the annual deaths that occur each year [39, 40]. An observed increase in NCDs parallels a rise in life expectancy of the global population [41, 42]. Life expectancy is now approaching eighty years of age [43] with a one percent lowering in the age-adjusted death rate from the years 2000 through 2011 [44]. In regard to developing countries, India and China will observe an elderly population increase from five to ten percent over future years [16, 45]. Increased lifespan may be due to multiple factors that include efficient sanitation measures, greater access to healthcare, and broader public health measures that assist populations for the highest risk for disability (Table 1). Such healthcare policies can result in earlier and effective treatment for multiple chronic disorders [42, 46–55].

As a result of more effective healthcare policies combined with an increase in lifespan throughout the world, the prevalence of neurodegenerative disorders has increased [9, 29, 56–61]. Neurodegenerative disorders consist of over six hundred disease entities that result in death and disability [45, 59, 60, 62, 63]. Neurodegenerative disorders lead to disability and death in more than one billion individuals, approximately fifteen percent of the global population, and at least seven million individuals die each year from neurodegenerative disorders [64]. Interestingly, disease of the nervous system lead to treatment costs over $700 billion United States dollars (USD) in the United States (US) alone. This costs involve treatments for dementia, back pain, stroke, epilepsy, traumatic brain injury, and Parkinson’s disease (PD) (Figure 2). It is of interest to note that cognitive care is the greatest cost factor with more than $800 billion USD a year allotted for memory loss [40]. These financial considerations do not consider other expenses that are required to provide social outreach programs, adult living care, and companion care, since at least 60 million new health and social care workers will be needed [39, 40, 65].

Figure 2: The Impact of Metabolic Dysfunction on Neurodegenerative Disorders.

Metabolic disorders are tightly linked to the onset and progression of neurodegenerative disorders. These include Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. In addition, other disorders, such as the apolipoprotein E (APOE-ε4) gene and coronavirus disease 2019 (COVID-19) can foster the onset and susceptibility of these neurodegenerative disorders through underlying metabolic pathways.

Early assessment of cognitive loss has become a challenge. Recognition, diagnosis, and treatment may be delayed for twelve to eighteen months following the initial onset of symptoms [4, 66, 67]. Per reports of the World Health Organization [40], dementia is present in populations throughout the globe and it is now the 7^th leading cause of death [9, 67–70]. In regard to sporadic cases of Alzheimer’s disease (AD) (Figure 2), sporadic AD is expected to increase for the future and comprises almost all clinical cases [3, 48, 64, 71–73]. Sporadic AD affects at least 10% of the world’s population over the age of 65 [3, 5, 56, 72–76].

When one considers metabolic disorders such as DM, metabolic disorders affect all systems of the body and especially the central nervous system and the peripheral nervous system as well as other related systems with inflammatory and vascular [77] (Figure 1). DM can lead to both cortical and subcortical disease in the central nervous system to result in cognitive loss [3–5, 28, 78, 79]. DM can lead to insulin resistance and memory loss associated with AD [67, 80, 81]. Metabolic disorders that include DM also can affect impact stem cell proliferation [16, 32, 82–84], cytoprotective pathways [26, 30, 85], circadian rhythm pathways [3, 28, 53, 86–92], immune mediated pathways that involve microglia [93–99], and lifespan extension pathways that involve sirtuins [9, 27, 28, 100–109]. Furthermore, over 70% of diabetic individuals also have peripheral neuropathy. DM can result in peripheral nerve disorders [4, 110–112] and autonomic neuropathy [113]. DM also can lead to low-grade and acute inflammation n the immune and vascular systems [23, 33, 37, 114], endothelial dysfunction [47, 115, 116], cardiovascular disease [16, 27, 31, 117–124], and impairment of the neurovascular unit [9, 13, 26, 79, 85, 116, 125–127].

Figure 1: Metabolic and Neurodegenerative Disease Cellular Pathways.

A number of metabolic and neurodegenerative cellular pathways rely upon the mechanistic target of rapamycin (mTOR) and its associated pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and p70 ribosomal S6 kinase (p70S6K). Intimately linked to these pathways are trophic factors, such as erythropoietin (EPO), apoptosis, autophagy, and inflammation that can involve pyroptosis.

3. Novel Therapeutics for Neurodegenerative Disorders during Metabolic Disease

Metabolic disorders are intimately tied to neurodegenerative disorders. Early and targeted therapy can reduce the progression of DM and its detrimental effects on the nervous system, such as dementia onset [11, 29, 32, 52, 53, 67, 117, 128–130]. The implementation of pharmacotherapy and calorie intake monitoring can assist with the treatment of metabolic disorders and DM. However, in the attempt to limit hyperglycemic events, potential risks can ensue that can affect cellular organelles, decrease organ mass, and lead to neuronal loss through processes that involve autophagy [131, 132]. Current therapies targeted to prevent cognitive loss can have metabolic components, such as the removal of ß-amyloid (Aβ) in the brain [133] and the use of cholinesterase inhibitors [69, 75]. These may provide limited resolution of symptoms or modify disease progression over a brief or unknown period [66, 69, 134–136]. Hypertension, cardiovascular disease, low education in early life, and tobacco use also can affect cognitive decline [66, 67, 137]. Other work places attention on heightened physical activity to stabilize metabolic disease and neurodegenerative disorders linked to dementia and PD [2, 9, 19, 138, 139]. Metabolic disease that impacts the vascular system also can result in cognitive loss [41, 140–143]. With these considerations, new avenues of discovery are required for neurodegenerative disease coupled to metabolic disorders. These include targeted strategies for metabolic homeostasis, programmed cell death pathways, the mechanistic target of rapamycin (mTOR) and its associated pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), growth factor signaling with erythropoietin (EPO), and critical risk factors such as the apolipoprotein E (APOE-ε4) gene (Table 1).

4. Programmed Cell Death Pathways in Neurodegenerative and Metabolic Disease

Neuronal survival and onset of neurodegenerative disorders can be affected by programmed cell death pathways during metabolic dysfunction [144–148] (Figure 1). Programmed cell death involves a number of processes that can modulate inflammatory pathways during cellular metabolic dysfunction [4, 16, 23, 116, 124, 149]. In particular, apoptosis, autophagy, and pyroptosis can ultimately determine the fate of a cell [150–156].

Apoptosis has both an early and late phase [71]. The early phase consists of phosphatidylserine (PS) membrane asymmetry loss on the plasma membrane [157–161]. The later phase of apoptosis leads to deoxyribonucleic acid (DNA) degradation in the genome [108, 162–168]. Loss of membrane PS asymmetry can lead to microglia and inflammatory cells to identify, engulf, and remove injured cells [99, 157, 169, 170]. In the event that the activity of microglia can be blocked, PS membrane asymmetry is reversible and can permit remaining functional cells expressing membrane PS residues to be rescued [171–174]. Apoptotic cell death occurs as a result of a cascade activation of nucleases and proteases that involve caspases [50, 163, 175–180]. The destruction of cellular DNA is considered not to be reversible [134]. Modulation of apoptotic pathways can minimize cognitive loss during acute insults [34, 153, 166, 175, 181, 182]. Activation of anti-inflammatory pathways can prevent apoptotic cellular death and prevent the loss of cognition [74, 177].

Autophagy processes have been shown to recycle cytoplasmic organelles and components for eventual tissue remodeling [52, 72, 73, 150, 183–191]. Subtypes of autophagy processing include macroautophagy, microautophagy, and chaperone-mediated autophagy. Macroautophagy recycles organelles and sequesters cytoplasmic proteins and organelles into autophagosomes that combine with lysosomes for degradation and recycling [73, 192, 193]. Microautophagy refers to the process of lysosomal membranes invagination for the collection and digestion of cytoplasmic components [194]. Chaperone-mediated autophagy relies upon cytosolic chaperones to move cytoplasmic components across lysosomal membranes [195].

Autophagy-lysosome pathways have been identified during infectious process to lead to inflammatory cell injury, such as with the pathogen severe acute respiratory syndrome coronavirus (SARS-CoV-2) [35, 36, 196–200]. As a result, autophagy through inflammatory mediators can affect memory and cognition [28, 201, 202]. Autophagy activation can reduce tau and Aß neurotoxicity [203–205]. Autophagy can remove Aß levels in the brain as one possible component to limit memory loss [81, 135, 203].

Pyroptosis, another form of programmed cell death, that can oversee inflammatory pathways in the nervous system during metabolic disease [4, 13, 134, 166, 206–208]. Pyroptosis is initiated with the generation of a supramolecular complex, termed the pyroptosome or the inflammasome, that can promote caspase activation to include caspase 1, caspase 4, and caspase 5. Pyroptosis utilizes permeabilization of the plasma membrane through gasdermin protein family members. Gasdermin proteins contain both an N-terminal domain with intrinsic pore-forming properties and a C-terminal domain that can block the pore forming properties of the N-terminal domain. Disruption of the linker sequence that binds the N-terminal and the C-terminal domains allows the N-terminal domain fragment to generate pores in the plasma. Cellular membranes are then able to release pro-inflammatory cytokines such as interleukin-1 family members. Inflammatory factors, such as interleukin-1 family members, can modulate a balance in regard to assisting or hampering cell survival that involve gasdermin. Interleukin-1 family members are absent of a signal plasma membrane peptide that would permit their cellular release and therefore require gasdermin proteins to generate membrane pores [5, 209]. This opening of cell membrane pores can lead to the rupture of cell membranes, the release of cytokines, and other damage-associated molecular pattern (DAMP) molecules that includes DNA and adenosine triphosphate (ATP). DAMPs can lead to the activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in the canonical inflammasome pathways. The noncanonical inflammasome pathway is initiated by binding of lipopolysaccharide proteins that can be found on gram-negative bacteria leading to caspase 4 and caspase 5 activation. Pyroptosis, therefore, can lead to pro-inflammatory responses that can cause cytokine storm and cell death [210]. These factors also play a role during DM and diabetic wound healing. Pro-inflammatory mediators, such as the NLRP3 inflammasome, can activate caspase 1 and cytokines, result in metabolic stress, and cause cell death and poor wound healing [207]. During reactive oxygen species (ROS) release and exposure to oxidative stress [25, 83, 211–213], pyroptosis as can have a significant role to affect cognition, AD, and DM complications that include neuronal and vascular disease [9, 25, 35, 42, 72, 181, 214, 215].

5. The Mechanistic Target of Rapamycin (mTOR)

A 289-kDa serine/threonine protein kinase, the mechanistic target of rapamycin (mTOR) is encoded by a single gene FRAP1 [3, 64, 73, 152, 186, 216, 217]. mTOR also is known as the mammalian target of rapamycin and the FK506-binding protein 12-rapamycin complex-associated protein 1 [195]. The target of rapamycin (TOR) was initially discovered in Saccharomyces cerevisiae with the genes TOR1 and TOR2 [217]. The agent rapamycin is a macrolide antibiotic in Streptomyces hygroscopicus that blocks TOR and mTOR activity [116].

mTOR is a vital component of the protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) (Figure 1). mTORC1 contains Raptor, Deptor (DEP domain-containing mTOR interacting protein), the proline rich Akt substrate 40 kDa (PRAS40), and mammalian lethal with Sec13 protein 8, termed mLST8 (mLST8) [3, 64]. mTOR can control Raptor activity which can be blocked by rapamycin. Rapamycin may block the activity of mTORC1 by binding to immunophilin FK-506-binding protein 12 (FKBP12) that normally attaches to the FKBP12 -rapamycin-binding domain (FRB) at the carboxy (C) -terminal of mTOR and blocks the FRB domain of mTORC1 [71]. However, the mechanism of how rapamycin blocks mTORC1 activity with the interaction of the domain of FRB is unclear. One consideration may involve allosteric changes on the catalytic domain as well as the inhibition of phosphorylation of protein kinase B (Akt) and p70 ribosomal S6 kinase (p70S6K) [218]. mTORC1 appears to be more sensitive to inhibition by rapamycin than mTORC2, but chronic administration of rapamycin can inhibit mTORC2 activity as a result of the disruption of the assembly of mTORC2. Deptor, also an inhibitor, blocks mTORC1 activity by binding to the FAT domain (FKBP12 -rapamycin-associated protein (FRAP), ataxia-telangiectasia (ATM), and the transactivation/transformation domain-associated protein) of mTOR. PRAS40 blocks mTORC1 activity by limiting the association of p70 ribosomal S6 kinase (p70S6K) and the eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4EBP1) with Raptor [3, 71]. Akt is important in this pathway as a checkpoint since mTORC1 activity is increased once phosphorylation of PRAS40 occurs by Akt [50, 165, 219, 220]. This releases the binding of PRAS40 and Raptor to localize PRAS40 in the cell cytoplasm with the docking protein 14–3-3 [221–223]. mLST8 can promote the activity of mTOR [71]. This process involves the binding of p70S6K and 4EBP1 to Raptor.

Interestingly, mLST8 controls insulin signaling through the transcription factor FoxO3 [114]. It also is necessary for Akt and protein kinase C-α (PKCα) phosphorylation, and is required for Rictor to associate with mTOR [114]. mTORC1 is associated with metabolic disorders [11, 35, 224] and dementia [4, 28, 142]. mTORC1 can promote lipogenesis and fat storage [225], improve glucose homeostasis [226], and may increase pancreatic ß-cell mass [227].

mTORC2 is composed of Rictor, Deptor, the mammalian stress-activated protein kinase interacting protein (mSIN1), mLST8, and the protein observed with Rictor-1 (Protor-1) [3, 71, 106, 183, 228]. mTORC2 is involved in metabolic function [5, 11]. mTORC2 signaling is necessary for the maintenance of pancreatic β-cell proliferation and mass [229]. Absence of mTORC2 signaling results in insulin resistance, oxidative damage [230], and severe hyperglycemia [231]. mTORC2 also modulates cytoskeleton remodeling through PKCα and cell migration through the Rac guanine nucleotide exchange factors P-Rex1 and P-Rex2 and through Rho signaling. mTORC2 can foster the activity of protein kinases that includes glucocorticoid induced protein kinase 1 (SGK1), a member of the protein kinase A/protein kinase G/protein kinase C (AGC) family of protein kinases. Protor-1, a Rictor-binding subunit of mTORC2, can result in SGK1 activity [38]. mSin1 is necessary for the construction of mTORC2 and for mTORC2 to phosphorylate Akt [38]. Rictor and mSIN1 phosphorylate Akt at serine⁴⁷³ and foster threonine³⁰⁸ phosphorylation by phosphoinositide-dependent kinase 1 (PDK1) to increase cell survival.

6. The Mechanistic Target of Rapamycin (mTOR) and Programmed Cell Death

mTOR has a close association with apoptosis, autophagy and pyroptosis (Table 1). mTOR activation can block apoptotic cell death in the nervous system [232, 233]. Through mTOR activation, retinal ganglion cell regeneration can be fostered [234], microglia survival can increase during oxidative stress [235], and diabetic peripheral neuropathy can be limited[236]. Aß toxicity during mTOR activation can be blocked [34, 222, 237–239], vascular cell death is prevented [190, 240], neuroplasticity is fostered [241], mitochondria loss during oxidative stress is blocked [242], neuronal differentiation can be fostered [243], neonatal hypoxic injury is limited [244], and decreased apoptotic cell death occurs during ischemic stroke [175].

Autophagy activation can be neuroprotective under some conditions that involve mTOR blockade [5, 34, 45, 72, 73]. Cognitive loss may be limited with low calorie diets that foster autophagy and limit mTOR activity [245]. Activation of autophagy with decreased mTOR function can lead to improved memory and more robust insulin signaling that can increase Aß clearance [246]. Cognition and memory also may increase with tau clearance during autophagy activation and mTOR function that has been limited [205]. Autophagy activation during a reduction in mTOR activity can block mitochondrial loss [247], prevent dopamine cell loss [248], decrease reactive oxygen species release [249], and improve neuronal cell survival with glutamine dependent mechanisms [250]. In the setting of metabolic disorders such as DM, mTOR inhibition can increase cell survival during cerebral ischemia [251] and maintain a balance between pancreatic β-cell proliferation and cell size [229]. Other work suggests that dysregulation of autophagy can result in cognitive loss with AD, development of autism spectrum disorder [252], and the induction of DM [80]. Studies have shown that autophagy haploinsufficiency with deletion of Atg7 gene in mouse models of obesity causes elevated lipids, insulin resistance, and inflammation [253]. Autophagic protein loss of Atg7, Atg5, and LC3 can be responsible for diabetic nephropathy [254]. Autophagy offers protection by removing misfolded proteins and mitochondria that cannot function to protect β-cell function and prevent DM development [255]. Exercise in murine models has been demonstrated to increase autophagy activation and promote glucose homeostasis [256]. This may occur as a result of improved insulin sensitivity [257] and reducing microglial activity in the setting of acute glucose changes [93].

Yet, a balance between autophagy and mTOR pathways may be necessary to promote the unction of cells. mTOR activity may be required since aberrations in mTOR activity can lead to cognitive loss [71, 73, 258]. Activation of autophagy can result in ROS insults to mitochondria, lead to the death of endothelial progenitor cells, and block new blood vessel formation during elevated glucose exposure [259]. Activation of autophagy at times may result in neuronal cell death [260]. Autophagy activation also can lead to cardiac and liver tissue injury in diabetic rats during diet modification that seeks to maintain glucose homeostasis [261]. During elevated glucose levels, advanced glycation end products (AGEs), proteins that can result in complications during DM, can result in the activation of autophagy and vascular smooth muscle proliferation that can result in atherosclerosis [262] as well as cardiomyopathy [263]. Autophagy with high glucose levels can lead to endothelial progenitor cell death, mitochondrial oxidative stress [264, 265], and inhibit angiogenesis [259]. Trophic factors, such as EPO, that lead to mTOR activation while reducing autophagic processes can increase neuronal and vascular cell survival in the nervous system [162, 220, 266]. EPO can control mTOR pathways, to include PRAS40 and Akt, and result in improved neuronal survival [221, 267–269]. mTOR activation has been shown to be vital for interneuron progenitor growth in the brain during autophagy inhibition [270].

mTOR also plays a significant role in multiple metabolic pathways [3, 11, 28, 36]. Through the mTOR pathways of p70S6K and 4EBP1 can result in the secretion of insulin in pancreatic β-cells as well as promote the resistance in murine models to β-cell streptozotocin toxicity and obesity [227]. Yet, loss of p70S6K activity leads to insulin insensitivity to glucose secretion, hypo-insulinemia, glucose intolerance, and reductions in pancreatic β-cell size [271]. Activation of mTOR in patients with metabolic syndrome has been shown to be decreased and potentially account for insulin resistance with a heightened risk of vascular thrombosis [272]. Activation of mTOR pathways has been tied pancreatic β- cell protection against cholesterol-induced apoptosis [273], increased protection of neurons in models of DM [274], and decreased glucolipotoxicity [275]. mTOR inhibition can result in insulin resistance, limited β-cell function, and reduced secretion of insulin associated with DM [276]. Loss of mTOR activity can raise mortality in murine models of DM [277]. In skeletal muscle, translocation of glucose transporters to the plasma membrane are affected during blockaded of mTOR [278].

Under some conditions, memory function can be protected during mTOR activation. mTOR activity can control insulin signaling in AD experimental models and promote astrocyte survival [279], maintain glucose homeostasis [226], and reduce endothelial cell dysfunction during hyperglycemia [280]. It is believed that part of the benefits of the Mediterranean diet may be a result of mTOR. mTOR can limit Aβ toxicity in astrocytes that may be linked to the onset of AD through Akt activation that is derived from consumption of polyphenol of olives and olive oil [279].

7. Metabolic and Neurodegenerative Disease Mediated by mTOR Pathways

The AMP activated protein kinase (AMPK), a pathway of mTOR, has a central role in metabolic disease, neurodegenerative disorders, infections, and inflammation [11, 101, 106, 188, 281, 282] (Figure 1). AMPK oversees mTORC1 activity through the hamartin (tuberous sclerosis 1)/tuberin (tuberous sclerosis 2) (TSC1/TSC2) complex that inhibits mTORC1 function [101]. Modulation of the TSC1/TSC2 complex also can be overseen though phosphoinositide 3-kinase (PI 3-K), Akt, and its phosphorylation of TSC2. Extracellular signal-regulated kinases (ERKs), protein p90 ribosomal S6 kinase 1 (RSK1), and glycogen synthase kinase −3β (GSK-3β) can control TSC1/TSC2 complex activity as well. TSC2 functions as a GTPase-activating protein (GAP) that changes G protein Rheb (Rheb-GTP) into the inactive GDP-bound form (Rheb-GDP). During Rheb-GTP activation, Rheb-GTP associates with Raptor to oversee the binding of 4EBP1 to mTORC1 and increase mTORC1 activity [283]. AMPK phosphorylates TSC2 to increase GAP activity to change Rheb-GTP into the inactive Rheb-GDP and to limit mTORC1 activity [11].

AMPK is significantly involved in both cellular metabolism and programmed cell death. AMPK modulates mitochondrial homeostasis and insulin resistance [4]. During dietary restriction associated with lifespan increases[284], AMPK can change cellular metabolism to shift to oxidative metabolism that is protective [285]. AMPK can be required for resistance to senescence for mesenchymal stem cells [286] and can increase survival for endothelial progenitor cells during hyperglycemia [287, 288]. Anti-senescence cell activation may be fostered through mTOR inhibition, AMPK activation, and increased autophagic flux [289]. AMPK activation can facilitate clearance of Aß [290] and tau [205] in the brain, lead to memory improvement in models of AD and DM [291], promote pathways for healthy aging [90, 292], reduce Aß neurotoxicity [293], and reduce inflammation in neurodegenerative disorders [45, 64].

AMPK leads to activation of autophagy to oversee cellular function and cellular metabolism [3, 5, 9, 294]. AMPK activity can be necessary to enhance endothelial cell survival during elevated glucose levels [280] and increase basal autophagy activity [150, 295]. AMPK oversees apoptosis and autophagy during oxidative stress cell injury [296, 297] and coronary artery disease [298]. AMPK also functions through growth factor cell protection. EPO enhances neuronal cell function and survival through AMPK activity and increased activity of autophagy [299]. EPO employs AMPK and mTOR activities to increase cell survival under conditions of inflammation [266, 300, 301] and oxidative stress [238]. Importantly, growth factor exposure and concentration with EPO exposure can affect AMPK and mTOR activity to alleviate detrimental effects of oxidative stress [221, 302]. As a result, it appears that a precise balance of mTOR activity is needed since elevated EPO levels can lead to cell loss and limit mTOR activity [303].

In the treatment of DM with metformin and biguanides, AMPK also is critical to reduce disorders such as peripheral neuropathy, demyelinating disease, and cognitive loss [28, 35, 304, 305]. Metformin blocks mTOR activity, promotes autophagy, and may function at times in an AMPK-independent manner [306]. Metformin reduces lipid peroxidation in the spinal cord and brain. These processes can be accompanied by reduced caspase activity to enhance cell survival [307]. AMPK pathways also may accelerate myelin recovery in animal models of multiple sclerosis [308]. Interestingly, metformin has recently been shown to reduce disability in patients with obesity or diabetic patients during coronavirus disease 2019 (COVID-19) [20, 309].

8. Assessing the Underlying Mechanisms for Neurodegenerative Disease Linked to Metabolic Dysfunction

There are a number of underlying mechanisms with disease of the nervous system related to cellular metabolic dysfunction. In regards to AD, the loss of cognition, the existence of metabolic disease, expression of the ε4 allele of the apolipoprotein E (APOE-ε4) gene, as well as the presence of severe acute respiratory syndrome (SARS) -CoV-2 (SARS-CoV-2) can be important clinical targets for these disorders [3, 34, 35, 57, 68, 77, 143, 194, 288, 310–317]. Individuals with the APOE-ε4 gene can have an increased risk of late-onset AD [190, 204, 318–320] (Figure 1). Apolipoprotein E (APOE) is produced in the liver. It is critical for cellular metabolism by overseeing lipid homeostasis and the transport of triglycerides, cholesterol, and phospholipids in the body [78, 321]. In the central nervous system, APOE is formed in astrocytes and facilitates through APOE receptors to transfer cholesterol to neurons [80, 190]. APOE also can help with the removal of Aβ in the brain (Table 1). It is important to recognize though that the isoform APOE-ε4 is not effective in the removal of Aβ which may result in increased risk for the onset of AD [80, 318, 322]. If two ε4 alleles are present in an individual, they can have almost 20 times the risk for acquiring AD. PS membrane exposure [323–326], part of the initial program in apoptotic cell death, can be related to Aβ aggregation. Studies suggest that some APOE isoforms can block the aggregation of Aβ through PS membrane exposure. Unfortunately, this does not occur for the isoform APOE-ε4 [327], but APOE-ε4 can increase mTOR activity [328, 329]. The effect of APOE-ε4 on mTOR and subsequently on autophagy flux has been associated with AD onset and cerebrovascular disease as a result of possible deficits in synaptic plasticity [316].

APOE-ε4 also has other effects related to infectious processes, COVID-19, and memory loss. More than twenty-two viral diseases have been identified to cause increased risk of neurodegenerative disorders, many leading to cognitive loss [330]. APOE-ε4 can foster the susceptibility of viral infection and cerebrovascular disease during COVID-19 [331] that involves the β-coronavirus family virion, SARS-CoV-2 [28, 35, 197, 305, 332, 333]. Coronaviruses are ribonucleic acid (RNA) viruses and are members of the family of Coronaviridae and the subfamily of Orthocoronavirinae [28, 334]. SARS-CoV-2 attaches to host cells, such as in the nasal epithelial region and the brain. Subsequently, the viron results in an increased response of the immune system [335]. Memory loss can follow after infection with SARS-CoV-2 [28, 35, 336]. The impairment in cognitive function can be part of a long-COVID syndrome [198]. Long-COVID, also termed as long-haul COVID, post-acute COVID-19, and chronic COVID, represents long-term effects that can occur following acute SARS-CoV-2 infection. There are a number of mechanisms that can account for long-COVID that involves metabolic pathways, oxidative stress, apoptosis, autophagy, mitochondrial dysfunction, cytokine release [56, 68, 186, 188, 337, 338]. Given the significance of APOE-ε4 in metabolism and autophagy processing, APOE-ε4 recently has been linked to the effects of long-COVID and cognitive loss [68]. Individuals with two ε4 alleles of APOE-ε4 have decreased expression of antiviral defense genes and experience heightened neuroinflammation and microvascular injury in the brain [319]. As a result, APOE-ε4 during SARS-CoV-2 infection and long COVID can lead to memory loss and cerebrovascular disease in the nervous system [19, 45, 71, 188, 339, 340].

PD is a progressive neurodegenerative disorder and is considered the second most common nervous system disease when compared to AD [71, 148, 194, 341]. PD is a movement disorder that leads to resting tremor, rigidity, and bradykinesia. It is characterized by the loss of dopaminergic neurons in the substantia nigra. More than 10 million individuals suffer from PD in the world and PD affects at least 4 percent of individuals over the age of 60 in the world. This number of individuals is expected to double by the year 2030 and presently 50,000 new cases for PD present each year in the US [45, 53, 217, 342]. In addition, at least $52 billion United States (US) dollars are spent in the US alone per year with an annual cost per patient that approaches approximately $25,000 US dollars per year.

There are a number of cellular pathways that can impact the onset and progression of PD [5, 53, 137, 342]. mTOR is one particular pathway [30, 53, 142]. In models with dopaminergic cells, activation of mTOR and p70S6K or the down-regulation of 4EBP1 can offer protection against oxidative stress [343]. Protein kinase B (Akt) pathway activation [165, 190, 193] with mTOR can block methamphetamine neurotoxicity in dopaminergic neurons [344]. PD toxic mimetics have been shown to suppress mTOR and p70S6K activity [345].

Modulation of autophagy and metabolism is another mechanism that can affect PD [134, 150, 151, 194, 346]. Autophagy can remodel cells and tissues through the recycling of cytoplasmic organelles [9, 13, 38, 347, 348]. Autophagy may protect neurons in PD through the maintenance of mitochondrial homeostasis, metabolic pathways [349–351], and even during elevated glucose levels [352]. Flavonoid metabolism in nutrients and diet may have a beneficial effect on PD [85]. However, in some cases, autophagy may be detrimental to dopamine neurons since blockade of autophagy with activation of mTOR can prevent dopaminergic neuronal injury during oxidative stress exposure [353]. Additional work addresses the role of α-synuclein toxicity in PD to support the premise that induction of autophagy degrades and eliminates α-synuclein to protect dopaminergic neurons [241, 354]. Mutation of α-synuclein and accumulation of wild-type α-synuclein in dopaminergic neurons has been tied to the onset and progression of PD [30]. Pathways of the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) also may be linked to autophagy in PD to foster neuroprotection [52, 71, 355]. Small non-coding ribonucleic acids (RNAs), termed microRNAs (miRNAs), may be important in PD as well [101, 120, 356–359]. MiRNAs consist of 19–25 nucleotides [19, 101, 120, 199, 360] and can modulate gene expression by silencing targeted messenger RNAs (mRNAs) translated by specific genes [67, 233, 361–363]. miRNAs can work in conjunction with mTOR, autophagy, and SIRT1 to modulate neurodegenerative processes [233, 356, 364].

In addition to AD and PD, cellular metabolic pathways, mTOR, and programmed cell death, such as autophagy, are involved in neurodegenerative disorders that involve Huntington’s disease (HD) (Figure 2) [134, 365, 366]. Metabolic pathways can be altered during HD [142, 367–371]. HD is the result of mutations leading to the polyglutamine tract expansion of CAG in the huntingtin (Htt) gene. mTOR can interact with mHtt and affect the course of HD [372]. Inhibition of mTOR activity can result in the induction of autophagy and the removal of proteins with long polyglutamine or polyalanine expansions [373]. Modulation of autophagy is important in HD to reduce mitochondrial dysfunction and improve motor function [134, 366]. Although mHtt can cellular metabolism signaling in pancreatic cells [374], mHtt can increase the activity of mTORC1 and increased mTORC1 activity can accelerate the onset of the loss of motor coordination and premature death in murine models of HD [375]. Blockade of mTORC1 alone may not be sufficient to alter autophagy or mHtt accumulation. Some studies suggest that combined inhibition of mTORC1 and mTORC2 is required for autophagy and the reduction of mHtt accumulation [376]. Studies in murine models of HD suggest that prevention of motor performance decline may be linked to decreasing the activity of p70S6K that improves muscle function instead of changes in cerebral mHtt accumulation and neuronal protection [377]. Importantly, complete elimination of mTOR activity during HD may not be beneficial requiring careful modulation for robust clinical efficacy. In HD patients and in rodent models of HD, the expression of Rhes, an mTOR activator in the striatum, is reduced [366]. Activation of mTORC1 protects against striatal atrophy, mitochondrial dysfunction, impaired dopamine signaling, and results in the induction of autophagy [366]. Furthermore, flavonoid metabolism may also protect neurons in HD[30, 85].

9. Future Considerations

Both metabolic disease and neurodegenerative disorders are significant healthcare concerns that can affect multiple disorders of the nervous system such as AD. PD, and HD (Table 1). The prevalence of DM is increasing and 700 million individuals are expected to suffer from DM by the year 2045 [6]. In addition, 7 million individuals greater than 18 years of age are undiagnosed with DM. Treatments that target tight monitoring of serum glucose, careful calorie intake assessment, and pharmaceuticals that can modulate glucose homeostasis can aide in controlling metabolic disorders. Yet, they cannot reverse the progression of metabolic dysfunction or reverse risks associated with decrease organ mass, cellular organelle injury, and neuronal cell loss through processes that involve autophagy. Of equal concern is the link of metabolic dysfunction to the onset and progression of neurodegenerative disorders that involve cognitive loss, AD, PD, and HD, all of which have limited treatment options. As a result, innovative treatment strategies are warranted and can include cellular metabolic pathways, apoptosis, autophagy, pyroptosis, mTOR, AMPK, trophic factor signaling with EPO, and the APOE-ε4 gene (Figure 1).

Investigations targeting mTOR as a basis for elucidating new treatments for metabolic dysfunction and neurodegenerative disorders can be indispensable. In conditions such as AD, activation of mTOR can reduce Aß toxicity in the nervous system. Growth factors, such as EPO, can provide cellular protection against neurodegeneration and metabolic instability through the activation of mTOR. Furthermore, mTOR components, such as mLST8, can modulate insulin signaling to maintain glucose homeostasis, mTORC1 can foster lipogenesis and fat storage, and improve glucose homeostasis, and mTORC2 signaling is required for the maintenance of pancreatic β-cell proliferation and mass. AMPK inhibition with active mTOR signaling can be required to limit Aβ toxicity, provide protection of pancreatic islet cells, and block nervous system inflammation. Yet, we also see that autophagy activation with an associated decrease in mTOR activity may be required for neuronal cell protection. Autophagy activation with blocked mTOR activity can lead to enhanced memory and improved insulin signaling that can increase Aß clearance in the nervous system. AMPK activation during mTOR inhibition can lead to memory retention, limit lipid accumulation and obesity, and result in increased cell survival. Furthermore, loss of autophagy may further the onset of cortical and memory dysfunction during metabolic disease and AD. These observations indicate the need for precision in the control of mTOR pathways to achieve a balance for optimal clinical outcome. Recent clinical studies may support this as well since immunotherapies targeted against Aß clearance for AD are successful in eliminating Aß in the brain, but the degree of clinical improvement achieved is at a much lower degree that does not correlate with the significant Aß clearance [133], suggesting that underlying cellular pathways may not be properly balanced. Similar considerations are evident for PD and HD. For example, in HD, decreased activity of p70S6K, an mTOR component, improves muscle function and neuronal protection, but in other scenarios activation of mTORC1 is necessary to prevent striatal atrophy, mitochondrial dysfunction, and impaired dopamine signaling.

The recognition that mTOR pathways, such as AMPK, form an intersection between metabolic and neurodegenerative pathways is vital in the development of future strategies for these disorders. APOE-ε4 is a prominent example of this, since APOE-ε4 oversees lipid homeostasis and the transport of triglycerides, cholesterol, and phospholipids but also is an important risk factor for developing AD. APOE-ε4 impacts mTOR signaling, increases mTOR activity, and affects autophagy flux that increases the risk for AD development. Aβ accumulation in the CNS is a result of the inability of APOE-ε4 to control apoptotic signaling with PS membrane exposure. APOE-ε4 also may promote cognitive loss, long COVID syndrome, and increase the susceptibility of viral infections and brain hemorrhages. As a central player in this scheme for new therapeutic avenues, mTOR may offer a number of innovative strategies to treat metabolic disorders tied to neurodegenerative diseases such as AD, PD, and HD given that the complexity and necessary balance for these pathways are fully comprehended.