scholarly journals Possible Clues for Brain Energy Translation via Endolysosomal Trafficking of APP-CTFs in Alzheimer’s Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Senthilkumar Sivanesan ◽  
Ravi Mundugaru ◽  
Jayakumar Rajadas
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ketone Bodies ◽  
Brain Regions ◽  
Pentose Phosphate ◽  
Lactate Shuttle ◽  
Carboxy Terminal ◽  
Brain Energy

Vascular dysfunctions, hypometabolism, and insulin resistance are high and early risk factors for Alzheimer’s disease (AD), a leading neurological disease associated with memory decline and cognitive dysfunctions. Early defects in glucose transporters and glycolysis occur during the course of AD progression. Hypometabolism begins well before the onset of early AD symptoms; this timing implicates the vulnerability of hypometabolic brain regions to beta-secretase 1 (BACE-1) upregulation, oxidative stress, inflammation, synaptic failure, and cell death. Despite the fact that ketone bodies, astrocyte-neuron lactate shuttle, pentose phosphate pathway (PPP), and glycogenolysis compensate to provide energy to the starving AD brain, a considerable energy crisis still persists and increases during disease progression. Studies that track brain energy metabolism in humans, animal models of AD, and in vitro studies reveal striking upregulation of beta-amyloid precursor protein (β-APP) and carboxy-terminal fragments (CTFs). Currently, the precise role of CTFs is unclear, but evidence supports increased endosomal-lysosomal trafficking of β-APP and CTFs through autophagy through a vague mechanism. While intracellular accumulation of Aβ is attributed as both the cause and consequence of a defective endolysosomal-autophagic system, much remains to be explored about the other β-APP cleavage products. Many recent works report altered amino acid catabolism and expression of several urea cycle enzymes in AD brains, but the precise cause for this dysregulation is not fully explained. In this paper, we try to connect the role of CTFs in the energy translation process in AD brain based on recent findings.

scholarly journals STIM1 deficiency is linked to Alzheimer’s disease and triggers cell death in SH-SY5Y cells by upregulation of L-type voltage-operated Ca2+ entry

2018 ◽  
Vol 96 (10) ◽  
pp. 1061-1079 ◽  
Author(s):  
Carlos Pascual-Caro ◽  
Maria Berrocal ◽  
Aida M. Lopez-Guerrero ◽  
Alberto Alvarez-Barrientos ◽  
Eulalia Pozo-Guisado ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Protein Expression ◽  
Transmembrane Domain ◽  
Neuroblastoma Cell ◽  
Disease Patient ◽  
List Type

Abstract STIM1 is an endoplasmic reticulum protein with a role in Ca2+ mobilization and signaling. As a sensor of intraluminal Ca2+ levels, STIM1 modulates plasma membrane Ca2+ channels to regulate Ca2+ entry. In neuroblastoma SH-SY5Y cells and in familial Alzheimer’s disease patient skin fibroblasts, STIM1 is cleaved at the transmembrane domain by the presenilin-1-associated γ-secretase, leading to dysregulation of Ca2+ homeostasis. In this report, we investigated expression levels of STIM1 in brain tissues (medium frontal gyrus) of pathologically confirmed Alzheimer’s disease patients, and observed that STIM1 protein expression level decreased with the progression of neurodegeneration. To study the role of STIM1 in neurodegeneration, a strategy was designed to knock-out the expression of STIM1 gene in the SH-SY5Y neuroblastoma cell line by CRISPR/Cas9-mediated genome editing, as an in vitro model to examine the phenotype of STIM1-deficient neuronal cells. It was proved that, while STIM1 is not required for the differentiation of SH-SY5Y cells, it is absolutely essential for cell survival in differentiating cells. Differentiated STIM1-KO cells showed a significant decrease of mitochondrial respiratory chain complex I activity, mitochondrial inner membrane depolarization, reduced mitochondrial free Ca2+ concentration, and higher levels of senescence as compared with wild-type cells. In parallel, STIM1-KO cells showed a potentiated Ca2+ entry in response to depolarization, which was sensitive to nifedipine, pointing to L-type voltage-operated Ca2+ channels as mediators of the upregulated Ca2+ entry. The stable knocking-down of CACNA1C transcripts restored mitochondrial function, increased mitochondrial Ca2+ levels, and dropped senescence to basal levels, demonstrating the essential role of the upregulation of voltage-operated Ca2+ entry through Cav1.2 channels in STIM1-deficient SH-SY5Y cell death. Key messages STIM1 protein expression decreases with the progression of neurodegeneration in Alzheimer’s disease. STIM1 is essential for cell viability in differentiated SH-SY5Y cells. STIM1 deficiency triggers voltage-regulated Ca2+ entry-dependent cell death. Mitochondrial dysfunction and senescence are features of STIM1-deficient differentiated cells.

scholarly journals Factors underlying cognitive decline in old age and Alzheimer’s disease: the role of the hippocampus

2017 ◽  
Vol 28 (7) ◽  
pp. 705-714 ◽  
Author(s):  
Wafa Jaroudi ◽  
Julia Garami ◽  
Sandra Garrido ◽  
Michael Hornberger ◽  
Szabolcs Keri ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Personality Traits ◽  
Old Age ◽  
Brain Regions ◽  
Personality Factors ◽  
Associated Symptoms ◽  
Lifestyle Patterns

AbstractThere are many factors that strongly influence the aetiology, development, and progression of cognitive decline in old age, mild cognitive impairment (MCI), and Alzheimer’s disease (AD). These factors include not only different personality traits and moods but also lifestyle patterns (e.g. exercise and diet) and awareness levels that lead to cognitive decline in old age. In this review, we discuss how personality traits, mood states, and lifestyle impact brain and behaviour in older adults. Specifically, our review shows that these lifestyle and personality factors affect several brain regions, including the hippocampus, a region key for memory that is affected by cognitive decline in old age as well as AD. Accordingly, appropriate recommendations are presented in this review to assist individuals in decreasing chances of MCI, dementia, AD, and associated symptoms.

scholarly journals Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases

2020 ◽  
Vol 21 (22) ◽  
pp. 8767
Author(s):  
Nicole Jacqueline Jensen ◽  
Helena Zander Wodschow ◽  
Malin Nilsson ◽  
Jørgen Rungby
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Brain Metabolism ◽  
Ketone Bodies ◽  
Current Knowledge ◽  
Ketogenic Diets ◽  
Cognitive Benefits ◽  
The Brain

Under normal physiological conditions the brain primarily utilizes glucose for ATP generation. However, in situations where glucose is sparse, e.g., during prolonged fasting, ketone bodies become an important energy source for the brain. The brain’s utilization of ketones seems to depend mainly on the concentration in the blood, thus many dietary approaches such as ketogenic diets, ingestion of ketogenic medium-chain fatty acids or exogenous ketones, facilitate significant changes in the brain’s metabolism. Therefore, these approaches may ameliorate the energy crisis in neurodegenerative diseases, which are characterized by a deterioration of the brain’s glucose metabolism, providing a therapeutic advantage in these diseases. Most clinical studies examining the neuroprotective role of ketone bodies have been conducted in patients with Alzheimer’s disease, where brain imaging studies support the notion of enhancing brain energy metabolism with ketones. Likewise, a few studies show modest functional improvements in patients with Parkinson’s disease and cognitive benefits in patients with—or at risk of—Alzheimer’s disease after ketogenic interventions. Here, we summarize current knowledge on how ketogenic interventions support brain metabolism and discuss the therapeutic role of ketones in neurodegenerative disease, emphasizing clinical data.

The prion-like properties of amyloid-beta peptide and Tau: Is there any risk of transmitting Alzheimer's disease during neurosurgical interventions?

2020 ◽  
Vol 17 ◽  
Author(s):  
Padilla-Zambrano H ◽  
García-Ballestas E ◽  
Quiñones-Ossa GA ◽  
Sibaja-Perez A ◽  
Agrawal A ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prion Diseases ◽  
Amyloid Β ◽  
Public Health Issue ◽  
Amyloid Β Peptide ◽  
Neurosurgical Procedure ◽  
Beta Peptide

: Recent studies have recognized similarities between the peptides involved in the neuropathology of Alzheimer’s disease and prions. The Tau protein and the Amyloid β peptide represent the theoretical pillars of Alzheimer’s disease development. It is probable that there is a shared mechanism for the transmission of these substances and the prion diseases development; this presumption is based on the presentation of several cases of individuals without risk factors who developed dementia decades after a neurosurgical procedure. This article aims to present the role of Aβ and Tau, which underlie the pathophysiologic mechanisms involved in the AD and their similarities with the prion diseases infective mechanisms by means of the presentation of the available evidence at molecular (in-vitro), animal, and human levels that support the controversy on whether these diseases might be transmitted in neurosurgical interventions, which may constitute a wide public health issue.

C-terminal inhibition of tau assembly in vitro and in Alzheimer's disease

2000 ◽  
Vol 113 (21) ◽  
pp. 3737-3745 ◽  
Author(s):  
A. Abraha ◽  
N. Ghoshal ◽  
T.C. Gamblin ◽  
V. Cryns ◽  
R.W. Berry ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amino Acids ◽  
Disease Process ◽  
Brain Regions ◽  
Microtubule Binding ◽  
C Terminus ◽  
Microtubule Binding Domain ◽  
Tau Polymerization

Alzheimer's disease (AD) is, in part, defined by the polymerization of tau into paired helical and straight filaments (PHF/SFs) which together comprise the fibrillar pathology in degenerating brain regions. Much of the tau in these filaments is modified by phosphorylation. Additionally, a subset also appears to be proteolytically truncated, resulting in the removal of its C terminus. Antibodies that recognize tau phosphorylated at S(396/404)or truncated at E(391) do not stain control brains but do stain brain sections very early in the disease process. We modeled these phosphorylation and truncation events by creating pseudo-phosphorylation and deletion mutants derived from a full-length recombinant human tau protein isoform (ht40) that contains N-terminal exons 2 and 3 and all four microtubule-binding repeats. In vitro assembly experiments demonstrate that both modifications greatly enhance the rates of tau filament formation and that truncation increases the mass of polymer formed, as well. Removal of as few as 12 or as many as 121 amino acids from the C terminus of tau greatly increases the rate and extent of tau polymerization. However, deletion of an additional 7 amino acids, (314)DLSKVTS(320), from the third microtubule-binding repeat results in the loss of tau's ability to form filaments in vitro. These results suggest that only part of the microtubule-binding domain (repeats 1, 2 and a small portion of 3) is crucial for tau polymerization. Moreover, the C terminus of tau clearly inhibits the assembly process; this inhibition can be partially reversed by site-specific phosphorylation and completely removed by truncation events at various sites from S(320) to the end of the molecule.

scholarly journals A novel role for SHARPIN in amyloid-β phagocytosis and inflammation by peripheral blood-derived macrophages in Alzheimer’s disease

2019 ◽  
Author(s):  
Dhanya Krishnan ◽  
Ramsekhar N Menon ◽  
Mathuranath PS ◽  
Srinivas Gopala
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Cell ◽  
Macrophage Polarization ◽  
Amyloid Β ◽  
The Novel ◽  
Inflammatory Phenotype ◽  
Underlying Mechanisms

AbstractINTRODUCTIONDefective immune cell-mediated clearance of amyloid-beta (Aβ) and Aβ-associated inflammatory activation of immune cells are key contributors of Aβ accumulation and neurodegeneration in Alzheimer’s disease (AD), however, the underlying mechanisms remain elusive.METHODSDifferentiated THP-1 cells treated with Aβ and AD patient-derived macrophages were used as in-vitro model. The role of SHARPIN was analysed in differentiated THP-1 cells using siRNA-mediated knockdown followed by immunoblotting, ELISA, real-time PCR, immunoprecipitation and flow cytometry. Differentiated SHSY5Y cells were used to study inflammation-mediated apoptosis.RESULTSSHARPIN was found to regulate Aβ-phagocytosis and NLRP3 expression in THP-1 derived macrophages. Further, it was found to promote macrophage polarization to an M1 (pro-inflammatory) phenotype resulting in enhanced inflammation and associated neuronal death, demonstrated using in-vitro culture systems. SHARPIN expression by blood-derived macrophages was further found to be higher in the early stages of AD, which correlates with Aβ40/42 concentration in the plasma and age of the study subjects.DISCUSSIONThe novel protein, SHARPIN has been shown to play critical roles in regulation of Aβ-phagocytosis and inflammation in AD and the mechanism by which SHARPIN is activated by Aβ in macrophages has been elucidated.

scholarly journals Lower MR-indexed locus coeruleus integrity in autosomal-dominant Alzheimer’s disease is related to cortical tau burden and memory deficits

2020 ◽  
Author(s):  
Martin J. Dahl ◽  
Mara Mather ◽  
Markus Werkle-Bergner ◽  
Briana L. Kennedy ◽  
Yuchuan Qiao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
High Resolution ◽  
Locus Coeruleus ◽  
Autosomal Dominant ◽  
Brain Regions ◽  
Cognitive Testing ◽  
Autosomal Dominant Alzheimer’S Disease

AbstractAbnormally phosphorylated tau, an indicator of Alzheimer’s disease, begins to accumulate in the first decades of life in the locus coeruleus (LC), the primary source of cortical norepinephrine. Ensuing dysfunction in noradrenergic neuromodulation is hypothesized to contribute to Alzheimer’s progression. However, research into the role of the LC has been impeded by a lack of effective ways of assessing it in vivo. Advances in high-resolution brainstem magnetic resonance imaging (MRI) hold potential to investigate the association of locus coeruleus integrity and Alzheimer’s-related neuropathological markers in vivo.Leveraging a meta-analytical approach, we first synthesized LC localizations and dimensions across previously published studies to improve the reliability and validity of MR-based locus coeruleus detection. Next, we applied this refined volume of interest to determine whether MR-indexed LC integrity can serve as a marker for noradrenergic degeneration in early-onset Alzheimer’s disease. Eighteen participants (34.7±10.1 years; 9♀) with or known to be at-risk for mutations in genes associated with autosomal-dominant Alzheimer’s disease (ADAD) were investigated. Genotyping confirmed mutations in seven participants (PSEN1, n = 6; APP, n = 1), of which four were symptomatic. Participants underwent 3T-MRI, flortaucipir positron emission tomography (PET), and cognitive testing. LC MRI intensity, a non-invasive proxy for neuronal density, was semi-automatically extracted from high-resolution brainstem scans across the rostrocaudal extent of the nucleus.Relative to healthy controls, symptomatic participants showed lower LC intensity. This effect was pronounced in rostral segments of the nucleus that project to the mediotemporal lobe and other memory-relevant areas. Among carriers of ADAD-causing mutations, closer proximity to the mutation-specific median age of dementia diagnosis was associated with lower LC intensity. Leveraging a multivariate statistical approach, we revealed a pattern of LC-related tau pathology in occipito-temporo-parietal brain regions. Finally, higher locus intensity was closely linked to memory performance across a variety of neuropsychological tests.Our finding of diminished MR-indexed LC integrity in autosomal-dominant Alzheimer’s disease suggest a role of the noradrenergic system in this neurodegenerative disease.

scholarly journals Multi-regional Neurodegeneration in Alzheimer’s disease: Meta-analysis and data integration of transcriptomics data

2018 ◽  
Author(s):  
Karbalaei Reza ◽  
Rezaei-Tavirani Mostafa ◽  
Torkzaban Bahareh ◽  
Azimzadeh Sadegh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Metabolic Pathways ◽  
Analytical Study ◽  
Meta Analysis ◽  
Brain Regions ◽  
Regulatory Pathways ◽  
Transcriptomics Data ◽  
The Brain

AbstractAlzheimer’s disease (AD) is a complex neurodegenerative disease with various deleterious perturbations in regulatory pathways of various brain regions. Thus, it would be critical to understanding the role of different regions of the brain in initiation and progression of AD, However, owing to complex and multifactorial nature of this disease, the molecular mechanism of AD has yet to be fully elucidated. To confront with this challenge, we launched a meta-analytical study of current transcriptomics data in four different regions of the brain in AD (Entorhinal, Hippocampus, Temporal and Frontal) with systems analysis of identifying involved signaling and metabolic pathways. We found different regulatory patterns in Entorhinal and Hippocampus regions to be associated with progression of AD. We also identified shared versus unique biological pathways and critical proteins among different brain regions. ACACB, GAPDH, ACLY, and EGFR were the most important proteins in Entorhinal, Frontal, Hippocampus and Temporal regions, respectively. Moreover, eight proteins including CDK5, ATP5G1, DNM1, GNG3, AP2M1, ALDOA, GPI, and TPI1 were differentially expressed in all four brain regions, among which, CDK5 and ATP5G1 were enriched in KEGG Alzheimer’s disease pathway as well.

scholarly journals Conjugates of neuroprotective chaperone L-PGDS provide MRI contrast for detection of amyloid β-rich regions in live Alzheimer’s Disease mouse model brain

2020 ◽  
Author(s):  
Bhargy Sharma ◽  
Joanes Grandjean ◽  
Margaret Phillips ◽  
Ambrish Kumar ◽  
Francesca Mandino ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Mouse Brain ◽  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Brain Regions ◽  
Mri Contrast ◽  
Neuroprotective Function

AbstractEndogenous brain proteins can recognize the toxic oligomers of amyloid-β (Aβ) peptides implicated in Alzheimer’s disease (AD) and interact with them to prevent their aggregation. Lipocalin-type Prostaglandin D Synthase (L-PGDS) is a major Aβ-chaperone protein in the human cerebrospinal fluid. Here we demonstrate that L-PGDS detects amyloids in diseased mouse brain. Conjugation of L-PGDS with magnetic nanoparticles enhanced the contrast for magnetic resonance imaging. We conjugated the L-PGDS protein with ferritin nanocages to detect amyloids in the AD mouse model brain. We show here that the conjugates administered through intraventricular injections co-localize with amyloids in the mouse brain. These conjugates can target the brain regions through non-invasive intranasal administration, as shown in healthy mice. These conjugates can inhibit the aggregation of amyloids in vitro and show potential neuroprotective function by breaking down the mature amyloid fibrils.

scholarly journals Amplification, not spreading limits rate of tau aggregate accumulation in Alzheimer’s disease

2020 ◽  
Author(s):  
Georg Meisl ◽  
Yukun Zuo ◽  
Kieren Allinson ◽  
Timothy Rittman ◽  
Sarah DeVos ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Regions ◽  
Replication Rate ◽  
Promising Strategy ◽  
Human Brains ◽  
The Brain ◽  
Tau Aggregate ◽  
Rate Of Accumulation

AbstractBoth the replication of protein aggregates and their spreading throughout the brain are implicated in the progression of Alzheimer’s disease (AD). However, the rates of these processes are unknown and the identity of the rate-determining process in humans has therefore remained elusive. By bringing together chemical kinetics with measurements of tau seeds and aggregates across brain regions, we are able to quantify their replication rate in human brains. Remarkably, we obtain comparable rates in several different datasets, with 5 different methods of tau quantification, from seed amplification assays in vitro to tau PET studies in living patients. Our results suggest that the overall rate of accumulation of tau in neocortical regions is limited not by spreading between brain regions but by local replication, which doubles the number of seeds every ~5 years. Thus, we propose that limiting local replication constitutes the most promising strategy to control tau accumulation during AD.

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