Cross-disease analysis of Alzheimer’s disease and type-2 Diabetes highlights the role of autophagy in the pathophysiology of two highly comorbid diseases (original) (raw)
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A systems biology investigation of neurodegenerative dementia reveals a pivotal role of autophagy
Background: Neurodegenerative dementia comprises chronic and progressive illnesses with major clinical features represented by progressive and permanent loss of cognitive and mental performance, including impairment of memory and brain functions. Many different forms of neurodegenerative dementia exist, but they are all characterized by death of specific subpopulation of neurons and accumulation of proteins in the brain. We incorporated data from OMIM and primary molecular targets of drugs in the different phases of the drug discovery process to try to reveal possible hidden mechanism in neurodegenerative dementia. In the present study, a systems biology approach was used to investigate the molecular connections among seemingly distinct complex diseases with the shared clinical symptoms of dementia that could suggest related disease mechanisms. Results: Network analysis was applied to characterize an interaction network of disease proteins and drug targets, revealing a major role of metabolism and, predominantly, of autophagy process in dementia and, particularly, in tauopathies. Different phases of the autophagy molecular pathway appear to be implicated in the individual disease pathophysiology and specific drug targets associated to autophagy modulation could be considered for pharmacological intervention. In particular, in view of their centrality and of the direct association to autophagy proteins in the network, PP2A subunits could be suggested as a suitable molecular target for the development of novel drugs.
Diabetes Promotes Development of Alzheimer’s Disease Through Suppression of Autophagy
Journal of Alzheimer's Disease, 2019
Recent studies suggest that diabetes predisposes patients to develop neurodegenerative Alzheimer's disease (AD), although the underlying mechanisms have yet to be determined. Compromised autophagy of neuronal cells, which occurs in the early stages of AD, has been shown to enhance disease progression. However, autophagic regulation as a mechanism connecting diabetes and AD has not been shown before. Here, we found that streptozotocin (STZ)-induced diabetic rats exhibited poorer performance on the social recognition test, Morris water maze, and plus-maze discriminative avoidance task, compared to PBS-treated normoglycemic control rats, likely resulting from increased brain deposition of amyloid- peptide aggregates (A) and increased phosphorylation of tau protein, two pathological features of AD. Moreover, diabetes-induced AD-like behavioral and pathological changes were associated with a decrease in neuronal cell autophagy. Furthermore, compromised cell autophagy was recapitulated in vitro in neuronal cells cultured in high glucose conditions. Thus, our data suggest that hyperglycemia in diabetes may directly inhibit neuronal cell autophagy, which subsequently enhances AD-associated pathological progression.
Autophagy and Alzheimer's Disease: From Molecular Mechanisms to Therapeutic Implications
Frontiers in aging neuroscience, 2018
Alzheimer's disease (AD) is the most common cause of progressive dementia in the elderly. It is characterized by a progressive and irreversible loss of cognitive abilities and formation of senile plaques, composed mainly of amyloid β (Aβ), and neurofibrillary tangles (NFTs), composed of tau protein, in the hippocampus and cortex of afflicted humans. In brains of AD patients the metabolism of Aβ is dysregulated, which leads to the accumulation and aggregation of Aβ. Metabolism of Aβ and tau proteins is crucially influenced by autophagy. Autophagy is a lysosome-dependent, homeostatic process, in which organelles and proteins are degraded and recycled into energy. Thus, dysfunction of autophagy is suggested to lead to the accretion of noxious proteins in the AD brain. In the present review, we describe the process of autophagy and its importance in AD. Additionally, we discuss mechanisms and genes linking autophagy and AD, i.e., the mTOR pathway, neuroinflammation, endocannabinoid ...
Autophagy: A double-edged sword in Alzheimer's disease
Journal of …, 2012
Autophagy is a major protein degradation pathway that is essential for stress-induced and constitutive protein turnover. Accumulated evidence has demonstrated that amyloid-β (Aβ) protein can be generated in autophagic vacuoles, promoting its extracellular deposition in neuritic plaques as the pathological hallmark of Alzheimer's disease (AD). The molecular machinery for Aβ generation, including APP, APP-C99 and β-/γ-secretases, are all enriched in autophagic vacuoles. The induction of autophagy can be vividly observed in the brain at early stages of sporadic AD and in an AD transgenic mouse model. Accumulated evidence has also demonstrated a neuroprotective role of autophagy in mediating the degradation of aggregated proteins that are causative of various neurodegenerative diseases. Autophagy is thus widely regarded as an intracellular hub for the removal of the detrimental Aβ peptides and Tau aggregates. Nonetheless, compelling data also reveal an unfavorable function of autophagy in facilitating the production of intracellular Aβ. The two faces of autophagy on the homeostasis of Aβ place it in a very unique and intriguing position in AD pathogenesis. This article briefly summarizes seminal discoveries that are shedding new light on the critical and unique roles of autophagy in AD and potential therapeutic approaches against autophagy-elicited AD.
Role of autophagy in Alzheimer’s disease
Autophagy is a tightly regulated lysosomal degradation/recycling pathway, critical for cellular homeostasis, such as neuronal survival and death. Impaired autophagic function has been reported in several neurodegenerative diseases, such as Parkinson’s, Huntington’s and Alzheimer’s disease (AD). AD is the most common cause of dementia in the elderly and it is characterized by progressive memory loss and cognitive decline along with synaptic dysfunction. Accumulations of amyloid β (Aβ) and tau proteins are two major neuropathological hallmarks of AD. In addition, accumulation of autophagic vacuoles and other autophagic pathology are evident in dystrophic neurites of AD brains. A series of studies has suggested that autophagy is involved in metabolism of A and tau. Moreover, presenilin (PS), a core subunit of γ-secretase complex, has been demonstrated to play an important role in autophagy at the level of lysosomal proteolysis. In spite of several therapeutic approaches through modulation of autophagic pathway, inconsistent results among studies have made it difficult to determine whether autophagy induction will be beneficial or detrimental for AD pathogenesis. Therefore, roles of autophagy in AD need to be further investigated to develop therapeutic strategies in the future.
Modulation of autophagy as a therapeutic target for Alzheimer’s disease
Macroautophagy (autophagy) is a conserved cellular pathway that regulates the degradation of long-lived proteins, protein aggregates, and cellular organelles. Autophagy is essential for maintaining neuronal homeostasis; however, neuronal autophagic efficiency decreases with age. Therefore, aging is one of the greatest risk factors for development of Alzheimer's disease (AD), a slowly progressing form of neurodegeneration that develops over the course of 10--20 years prior to the onset of overt clinical symptoms. AD is defined neuropathologically by the presence of extracellular aggregates of the amyloidogenic protein amyloid--β (Aβ) and intracellular accumulation of the microtubule--associated protein tau. At end--stage Alzheimer's disease, abnormal autophagic pathology has been reported in human brain and in multiple mouse models of AD, suggesting that an intimate association may exist between neuronal autophagy stasis and Alzheimer's--related pathology. Here, we highlight recent evidence that the autophagic pathway plays a role in both the generation and clearance of the pathogenic Aβ protein and its precursors. The primary focus of this review is to examine the compelling research that highlights the autophagic pathway as a therapeutic target for AD and to discuss the therapeutic space around autophagy--regulating programs for AD. Finally, we propose that programs targeting autophagy regulation for AD ought to consider prophylactic or early stage intervention trials based on evidence against druggability of this pathway in late--stage disease.
A Molecular Bridge: Connecting Type 2 Diabetes and Alzheimer’s Disease
Type 2 diabetes (T2D) and Alzheimer's disease (AD) are complex diseases commonly associated with aging. Accumulating evidence indicates a connection between these two diseases at the molecular level. Much of what we currently know about T2D and AD is derived from in vivo and in vitro studies. However, further research and characterization of molecules is necessary to establish a strong connection between T2D and AD. In silico studies play a major role in finding non-evident patterns of gene expression and gene network connectivity. In this review, we give a brief introduction to T2D and AD and then describe the risk factors and molecules that are commonly associated with these diseases. Finally, we discuss the future directions and applications of bioinformatics that can provide greater insight into the relationship between these two diseases. Analysis and integration of high-throughput data on genomics, transcriptomics, proteomics and metabolomics from normal and disease tissues would be very useful to improve our understanding of the mechanism behind disease initiation and the connection between these two diseases. We encourage researchers to use bioinformatics approaches to identify genes and their regulatory pathways that are commonly affected in T2D and AD, as these genes and pathways could be potential biomarkers and targets for disease treatment.
Biochimica et biophysica acta, 2015
We aimed to investigate mitochondrial function, biogenesis and autophagy in the brain of type 2 diabetes (T2D) and Alzheimer's disease (AD) mice. Isolated brain mitochondria and homogenates from cerebral cortex and hippocampus of wild-type (WT), triple transgenic AD (3xTg-AD) and T2D mice were used to evaluate mitochondrial functional parameters and protein levels of mitochondrial biogenesis, autophagy and synaptic integrity markers, respectively. A significant decrease in mitochondrial respiration, membrane potential and energy levels was observed in T2D and 3xTg-AD mice. Also, a significant decrease in the levels of autophagy-related protein 7 (ATG7) and glycosylated lysosomal membrane protein 1 (LAMP1) was observed in cerebral cortex and hippocampus of T2D and 3xTg-AD mice. Moreover, both brain regions of 3xTg-AD mice present lower levels of nuclear respiratory factor (NRF) 1 while the levels of NRF2 are lower in both brain regions of T2D and 3xTg-AD mice. A decrease in mitoc...
Autophagy failure in Alzheimer's disease—locating the primary defect
Neurobiology of Disease, 2011
Autophagy, the major degradative pathway for organelles and long-lived proteins, is essential for the survival of neurons. Mounting evidence has implicated defective autophagy in the pathogenesis of several major neurodegenerative diseases, particularly Alzheimer's disease (AD). A continuum of abnormalities of the lysosomal system has been identified in neurons of the AD brain, including pathological endocytic pathway responses at the very earliest disease stage and a progressive disruption of autophagy leading to the massive buildup of incompletely digested substrates within dystrophic axons and dendrites. In this review, we examine research on autophagy in AD and evaluate evidence addressing the specific step or steps along the autophagy pathway that may be defective. Current evidence strongly points to disruption of substrate proteolysis within autolysosomes for the principal mechanism underlying autophagy failure in AD. In the most common form of familial early onset AD, mutant presenilin 1 disrupts autophagy directly by impeding lysosomal proteolysis while, in other forms of AD, autophagy impairments may involve different genetic or environmental factors. Attempts to restore more normal lysosomal proteolysis and autophagy efficiency in mouse models of AD pathology have yielded promising therapeutic effects on neuronal function and cognitive performance, demonstrating the relevance of autophagy failure to the pathogenesis of AD and the potential of autophagy modulation as a therapeutic strategy.