The programmed cell death that occurs as part of normal mammalian development was first observed nearly a century ago (Collin 1906). It has since been established that approximately half of all neurons in the neuroaxis and >99.9% of the total number of cells generated during the course of a human lifetime go on to die through a process of apoptosis (for review, see Datta and Greenberg 1998; Vaux and Korsmeyer 1999). The induction of developmental cell death is a highly regulated process and can be suppressed by a variety of extracellular stimuli. The purification in the 1950s of the nerve growth factor (NGF), which promotes the survival of sympathetic neurons, set the stage for the discovery that peptide trophic factors promote the survival of a wide variety of cell types in vitro and in vivo (Levi-Montalcini 1987). The profound biological consequences of growth factor (GF) suppression of apoptosis are exemplified by the critical role of target-derived neurotrophins in the survival of neurons and the maintenance of functional neuronal circuits. (Pettmann and Henderson 1998). Recently, the ability of trophic factors to promote survival have been attributed, at least in part, to the phosphatidylinositide 38-OH kinase (PI3K)/c-Akt kinase cascade. Several targets of the PI3K/c-Akt signaling pathway have been recently identified that may underlie the ability of this regulatory cascade to promote survival. These substrates include two components of the intrinsic cell death machinery, BAD and caspase 9, transcription factors of the forkhead family, and a kinase, IKK, that regulates the NF-kB transcription factor. This article reviews the mechanisms by which survival factors regulate the PI3K/c-Akt cascade, the evidence that activation of the PI3K/c-Akt pathway promotes cell survival, and the current spectrum of c-Akt targets and their roles in mediating c-Akt-dependent cell survival.

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Cellular survival: a play in three Akts

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

https://biblio.ugent.be/publication/8555786/file/8555788.pdf

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

The transcription factor CREB -- for 'cyclic AMP response element-binding protein' -- functions in glucose homeostasis, growth-factor-dependent cell survival, and has been implicated in learning and memory. CREB is phosphorylated in response to various signals, but how is specificity achieved in these signalling pathways?

Transcriptional regulation by the phosphorylation-dependent factor CREB

In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.

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Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012

Protein tyrosine phosphatase–1B (PTP-1B) has been implicated in the negative regulation of insulin signaling. Disruption of the mouse homolog of the gene encoding PTP-1B yielded healthy mice that, in the fed state, had blood glucose concentrations that were slightly lower and concentrations of circulating insulin that were one-half those of their PTP-1B+/+ littermates. The enhanced insulin sensitivity of the PTP-1B−/− mice was also evident in glucose and insulin tolerance tests. The PTP-1B−/− mice showed increased phosphorylation of the insulin receptor in liver and muscle tissue after insulin injection in comparison to PTP-1B+/+ mice. On a high-fat diet, the PTP-1B−/− and PTP-1B+/− mice were resistant to weight gain and remained insulin sensitive, whereas the PTP-1B+/+ mice rapidly gained weight and became insulin resistant. These results demonstrate that PTP-1B has a major role in modulating both insulin sensitivity and fuel metabolism, thereby establishing it as a potential therapeutic target in the treatment of type 2 diabetes and obesity.

https://science.sciencemag.org/content/sci/283/5407/1544.full.pdf

Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene.

SIRT3 deacetylates mitochondrial proteins, thereby enhancing their function. We have previously demonstrated that Sirt3 gene deletion leads to brain mitochondrial dysfunction and neuroinflammation. We also reported that silencing of Sirt3 gene in APP/PS1 mice results in exacerbation of insulin resistance, neuroinflammation and β amyloid plaque deposition. To further understand how metabolic syndrome and amyloid pathology interact, we performed RNA-seq analysis of the brain samples of APP/PS1/Sirt3-/- mice. Gene expression patterns were modulated in metabolic and inflammatory pathways by Sirt3 gene deletion, amyloid pathology, and the combination. Following Sirt3 gene deletion, a key finding was the decreased expression of insulin-degrading enzyme (IDE), an enzyme that regulates the levels of insulin and Aβ peptides. Western diet feeding of Sirt3-/- and APP/PS1 mice resulted in decrease of IDE protein, parallel to Sirt3 downregulation. Conversely, activation of SIRT3 by nicotinamide riboside in vivo and in vitro resulted in IDE upregulation. SIRT3 activation in vivo also increased the levels of neprilysin, another Aβ degrading enzyme and decreased the levels of BACE1 which generates Aβ peptide suggesting SIRT3's role in amyloid plaque reduction. Our findings provide a plausible mechanism linking metabolic syndrome and amyloid pathology. SIRT3 may be a potential therapeutic target to treat AD. 

/pdf/sirt3-deficiency-induced-down-regulation-of-insulin-ne720v24.pdf

Sirt3 deficiency induced down regulation of insulin degrading enzyme in comorbid Alzheimer’s disease with metabolic syndrome

Research studies centered on the biology, regeneration, and transplantation of islets continue to shed significant understanding on the development of different forms of diabetes and provide further impetus for the quest to find a “cure.” Diabetes is a manifestation of an inadequate mass of insulin-producing pancreatic beta-cells. While type 1 is characterized by complete loss of beta-cells due to autoimmune attack on them, type 2 is characterized by a relative deficiency of beta-cells due to a decreased compensation for insulin resistance [1, 2]. Restoring beta-cell mass and reversing diabetes can be accomplished by two approaches: either by endogenous regeneration of beta-cells or transplantation of beta-cells from exogenous sources; recent advancements in science and technology have facilitated progress in both. In the first approach, while efforts to expand mature beta-cells in vitro have been met with limited success, regeneration of beta-cells from embryonic and adult stem cells, or pancreatic progenitor cells, has shown promise [2]. Understanding the role of beta-cell-specific transcription factors in the transdifferentiation to beta-cell phenotype is critical to further progress. Pharmacological approaches, employing growth factors, hormones, and small molecules, have also been shown to boost beta-cell proliferation and function.

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Islet Cell Biology, Regeneration, and Transplantation

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Editorial Islet Cell Biology, Regeneration, and Transplantation

SIRT3, the primary mitochondrial deacetylase, regulates the functions of mitochondrial proteins including metabolic enzymes and respiratory chain components. Although SIRT3’s functions in peripheral tissues are well established, the significance of its downregulation in neurodegenerative diseases is beginning to emerge. SIRT3 plays a key role in brain energy metabolism and provides substrate flexibility to neurons. It also facilitates metabolic coupling between fuel substrate-producing tissues and fuel-consuming tissues. SIRT3 mediates the health benefits of lifestyle-based modifications such as calorie restriction and exercise. SIRT3 deficiency is associated with metabolic syndrome (MetS), a precondition for diseases including obesity, diabetes, and cardiovascular disease. The pure form of Alzheimer’s disease (AD) is rare, and it has been reported to coexist with these diseases in aging populations. SIRT3 downregulation leads to mitochondrial dysfunction, neuroinflammation, and inflammation, potentially triggering factors of AD pathogenesis. Recent studies have also suggested that SIRT3 may act through multiple pathways to reduce plaque formation in the AD brain. In this review, we give an overview of SIRT3’s roles in brain physiology and pathology and discuss several activators of SIRT3 that can be considered potential therapeutic agents for the treatment of dementia.

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A Promising Strategy to Treat Neurodegenerative Diseases by SIRT3 Activation

The Editorial on the Research Topic

Molecular Mechanism of Neuronal Dysfunction in the Diabetic Brain

Insulin signaling plays a significant role in the brain synaptic function. Insulin resistance is associated with reductions in cerebral glucose metabolism even in prediabetic individuals (1). Cognitive dysfunction in chronic diabetes is being recognized as a complication that needs to be seriously addressed. Epidemiological studies have also identified diabetes as a risk factor for Alzheimer’s disease (AD) (2, 3). The link between diabetes and AD is further supported by studies in animal models (3). Chronic hyperglycemia-induced accumulation of advanced glycation end products (AGEs) (4) and their receptor RAGE are among the mechanistic links between diabetes and AD (5). Soluble form of RAGE (sRAGE) acts as a decoy for RAGE and provides a counter-regulatory mechanism. Selvin et al. have reported that low levels of sRAGE increase the risk of diabetes and mortality (6). Decreased levels of sRAGE have been also observed in AD patients (7). In this special issue, six articles (three original reports and three reviews) highlight the interactions of these two aging-associated diseases from several angles.

van Dijk et al. describe AD as a complex, multifactorial disease that includes, but not limited to neuroinflammation, processing of amyloid precursor protein (APP) to amyloid β peptide, and tau protein hyperphosphorylation. The authors propose that these pathophysiologic mechanisms are propagated by obesity, metabolic syndrome, and type-2 diabetes mellitus. The authors assert that complex and interacting mechanisms are not yet completely understood and will require further analysis. This review discusses several of these interacting mechanisms in the animal models and compares them with clinical data, thus giving an overview about the current knowledge of diabetes and its possible relationship to AD. Vinik et al. have suggested that inflammatory cytokines as well as oxidative and nitrosative stress in diabetes play important roles in autonomic dysfunction (8). Pharmaceutical approaches suggested in this review article to restore autonomic function can also provide potential therapeutic strategies for targeting neurodegeneration in the brain.

Another review article by Sato and Morishita highlights the common brain pathologies of diabetes and AD. For example, diabetes is associated with reduced hippocampal volume due to neuronal loss and aberrant functional connectivity. Because insulin inhibits tau phosphorylation through negative regulation of GSK3β and protein phosphatase 2A, diabetes promotes the formation of neurofibrillary tangles as a result of tau hyperphosphorylation, an important pathological feature of AD. Defective brain glucose metabolism is another common feature of diabetes and AD because insulin signaling is altered by Aβ. Impaired cerebrovascular function in the diabetic brain can lead to blood–brain barrier (BBB) damage as in AD. Thus, diabetes can impair cognitive function by both Aβ/tau-dependent and -independent mechanisms.

In an intriguing report, van der Harg et al. highlight the association of diabetes, neuroinflammation, and AD. The authors examined whether neuroinflammation could be the mechanistic trigger to induce tau phosphorylation in the brain of diabetic animals. This study utilized two diabetic rat models, rats on a free-choice high-fat high-sugar (fcHFHS) diet that were insulin resistant and streptozotocin-treated rats that were insulin deficient. As expected, the streptozotocin-treated animals showed increased tau phosphorylation in the brain, whereas the fcHFHS diet-fed animals did not. Interestingly, neither of the diabetic animal models showed reactive microglia or increased GFAP and COX-2 levels, markers of inflammation, in the brain. These authors concluded that neuroinflammation is not the mechanism that explains the close connection between diabetes and AD in terms of Tau pathology.

Bartman et al. focus on another pathway involving glycogen synthase kinase-3, phosphatidylinositol 3-kinase (PI3K), and Wnt/β-catenin. Genetic deletion of both Gsk-3α and Gsk-3β in mouse embryonic stem cells (ESCs) appears to lead to the constitutive activation of the Wnt/β-catenin and insulin signaling pathways. This study compared the gene expression profiles in Gsk-3α−/− Gsk-3β−/− ESCs to mouse ESCs in which Wnt/β-catenin signaling or PI3K-dependent insulin signaling were constitutively active. Results showed that Wnt signaling had a greater effect on upregulated genes in the Gsk-3α−/−; Gsk-3β−/− ESCs, whereas PI3K-dependent insulin signaling was more responsible for the downregulation of genes in the same cells.

Hypoglycemia is a known side effect of insulin therapy in both type-1 and type-2 diabetes. Recurrent hypoglycemic (RH) episodes are of concern in diabetic patients and are the biggest obstacle to intensive insulin therapy aimed at tight glycemic control. McNay’s report (McNay) examined the impact of RH on the amygdala, which plays a key role in anxiety and mood. Animals in the RH group showed heightened anxiety as measured by significantly less time spent in the open arms during plus-maze testing. This observation was also accompanied by increased norepinephrine release in the basolateral amygdala (BLA), a marker for amygdala cognitive modulation. These findings are consistent with the clinical experience of diabetic patients, especially with respect to impaired mood control and increased anxiety.

Sebastiao et al. highlight an important therapeutic angle in the diabetes/AD connection. Although the primary goal of diabetes treatment is achieving normoglycemia, these authors indicate that this is not sufficient because of the CNS changes in diabetic patients that could go unnoticed over decades. To normalize these defects, we need to take advantage of the beneficial actions of antidiabetic drugs in the brain. It has been suggested that therapeutic strategies against diabetes might be also beneficial against AD. Especially, glucagon-like peptide-1 (GLP-1)-based therapies have shown promise in the treatment of AD because GLP-1 can pass through BBB. Velmurugan et al. have previously reported the neuroprotective actions of GLP-1 in human neuroprogenitor cell-derived neurons (9).

The reports in this special issue are, but a few, of the enormous amount of investigation into the association between neuroinflammation, diabetes, and AD. The life expectancy of people with diabetes is steadily increasing with the availability of several classes of drugs for managing diabetes, its complications, and glycemic control. Dementia among diabetic patients will be a major health problem in the upcoming years with intellectually challenging life styles. Beneficial actions of antidiabetic drugs in the brain need to be considered in long-term diabetes management.

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Subbiah Pugazhenthi

Papers

Sirt3 deficiency induced down regulation of insulin degrading enzyme in comorbid Alzheimer’s disease with metabolic syndrome

Islet Cell Biology, Regeneration, and Transplantation

Editorial Islet Cell Biology, Regeneration, and Transplantation

A Promising Strategy to Treat Neurodegenerative Diseases by SIRT3 Activation

Editorial: Molecular Mechanism of Neuronal Dysfunction in the Diabetic Brain.