scholarly journals Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer's disease brain

2021 ◽  
Author(s):  
Hans-Ulrich Klein ◽  
Caroline Trumpff ◽  
Hyun-Sik Yang ◽  
Annie J Lee ◽  
Martin Picard ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dna ◽  
Human Brain ◽  
Neurodegenerative Diseases ◽  
Late Onset ◽  
Multivariable Analysis ◽  
Amyloid Β ◽  
Brain Regions ◽  
Mtdna Copy Number

Mitochondrial dysfunction is a feature of neurodegenerative diseases, including Alzheimer's disease (AD). Using whole-genome sequencing, we assessed mitochondrial DNA (mtDNA) heteroplasmy levels and mtDNA copy number (mtDNAcn) in 1,361 human brain samples of five brain regions from three studies. Multivariable analysis of ten common brain pathologies identified tau pathology in the dorsolateral prefrontal cortex and TDP-43 pathology in the posterior cingulate cortex as primary drivers of reduced mtDNAcn in the aged human brain. Amyloid-β pathology, age, and sex were not associated with mtDNAcn. Further, there is evidence for a direct effect of mitochondrial health on cognition. In contrast, while mtDNA heteroplasmy levels increase by about 1.5% per year of life in the cortical regions, we found little evidence for an association with brain pathologies or cognitive functioning. Thus, our data indicates that mtDNA heteroplasmy burden is unlikely to be involved in the pathogenesis of late-onset neurodegenerative diseases.

scholarly journals Is There Any Evidence of Monocytes Involvement in Alzheimer’s Disease? A Pilot Study on Human Postmortem Brain

2021 ◽  
pp. 1-11
Author(s):  
Camelia-Maria Monoranu ◽  
Tim Hartmann ◽  
Sabrina Strobel ◽  
Helmut Heinsen ◽  
Peter Riederer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Human Brain ◽  
Amyloid Β ◽  
Occipital Lobe ◽  
Inflammatory Cells ◽  
Brain Regions ◽  
Postmortem Brain

Background: The role of neuroinflammation has become more evident in the pathogenesis of neurodegenerative diseases. Increased expression of microglial markers is widely reported in Alzheimer’s disease (AD), but much less is known about the role of monocytes in AD pathogenesis. In AD animal models, bone marrow-derived monocytes appear to infiltrate the parenchyma and contribute to the phagocytosis of amyloid-β depositions, but this infiltration has not been established in systematic studies of the human brain postmortem. Objective: In addition to assessing the distribution of different subtypes of microglia by immunostaining for CD68, HLA-DR, CD163, and CD206, we focused on the involvement of C-chemokine receptor type2 (CCR2) positive monocytes during the AD course. Methods: We used formalin-fixed and paraffin-embedded tissue from four vulnerable brain regions (hippocampus, occipital lobe, brainstem, and cerebellum) from neuropathologically characterized AD cases at different Braak stages and age-matched controls. Results: Only singular migrated CCR2-positive cells were found in all brain regions and stages. The brainstem showed the highest number of positive cells overall, followed by the hippocampus. This mechanism of recruitment seems to work less efficiently in the human brain at an advanced age, and the ingress of monocytes obviously takes place in much reduced numbers or not at all. Conclusion: In contrast to studies on animal models, we observed only a quite low level of myeloid monocytes associated with AD pathology. Furthermore, we provide evidence associating early microglial reactions carried out in particular by pro-inflammatory cells with early effects on tangle- and plaque-positive vulnerable brain regions.

Pharmacogenetics of Angiotensin-Converting Enzyme Inhibitors in Patients with Alzheimer's Disease Dementia

2018 ◽  
Vol 15 (4) ◽  
pp. 386-398 ◽  
Author(s):  
Fabricio Ferreira de Oliveira ◽  
Elizabeth Suchi Chen ◽  
Marilia Cardoso Smith ◽  
Paulo Henrique Ferreira Bertolucci
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Angiotensin Converting Enzyme ◽  
Cognitive Decline ◽  
Enzyme Inhibitors ◽  
Late Onset ◽  
Amyloid Β ◽  
Converting Enzyme ◽  
Converting Enzyme Inhibitors ◽  
Alzheimer’S Disease Dementia

Background: While the angiotensin-converting enzyme degrades amyloid-β, angiotensinconverting enzyme inhibitors (ACEis) may slow cognitive decline by way of cholinergic effects, by increasing brain substance P and boosting the activity of neprilysin, and by modulating glucose homeostasis and augmenting the secretion of adipokines to enhance insulin sensitivity in patients with Alzheimer’s disease dementia (AD). We aimed to investigate whether ACE gene polymorphisms rs1800764 and rs4291 are associated with cognitive and functional change in patients with AD, while also taking APOE haplotypes and anti-hypertensive treatment with ACEis into account for stratification. Methods: Consecutive late-onset AD patients were screened with cognitive tests, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic correlations were estimated for one year, considering APOE and ACE genotypes and haplotypes, and treatment with ACEis. Results: For 193 patients, minor allele frequencies were 0.497 for rs1800764 – C (44.6% heterozygotes) and 0.345 for rs4291 – T (38.9% heterozygotes), both in Hardy-Weinberg equilibrium. Almost 94% of all patients used cholinesterase inhibitors, while 155 (80.3%) had arterial hypertension, and 124 used ACEis. No functional impacts were found regarding any genotypes or pharmacological treatment. Either for carriers of ACE haplotypes that included rs1800764 – T and rs4291 – A, or for APOE4- carriers of rs1800764 – T or rs4291 – T, ACEis slowed cognitive decline independently of blood pressure variations. APOE4+ carriers were not responsive to treatment with ACEis. Conclusion: ACEis may slow cognitive decline for patients with AD, more remarkably for APOE4- carriers of specific ACE genotypes.

scholarly journals Tau and TDP-43 synergy: a novel therapeutic target for sporadic late-onset Alzheimer’s disease

GeroScience ◽  
2021 ◽  
Author(s):  
Caitlin S. Latimer ◽  
Nicole F. Liachko
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Hippocampal Sclerosis ◽  
Model Organism ◽  
Amyloid Β ◽  
Underlying Disease ◽  
Therapeutic Interventions ◽  
Disease Biology ◽  
Rapid Cognitive Decline

AbstractAlzheimer’s disease (AD) is traditionally defined by the presence of two types of protein aggregates in the brain: amyloid plaques comprised of the protein amyloid-β (Aβ) and neurofibrillary tangles containing the protein tau. However, a large proportion (up to 57%) of AD patients also have TDP-43 aggregates present as an additional comorbid pathology. The presence of TDP-43 aggregates in AD correlates with hippocampal sclerosis, worse brain atrophy, more severe cognitive impairment, and more rapid cognitive decline. In patients with mixed Aβ, tau, and TDP-43 pathology, TDP-43 may interact with neurodegenerative processes in AD, worsening outcomes. While considerable progress has been made to characterize TDP-43 pathology in AD and late-onset dementia, there remains a critical need for mechanistic studies to understand underlying disease biology and develop therapeutic interventions. This perspectives article reviews the current understanding of these processes from autopsy cohort studies and model organism-based research, and proposes targeting neurotoxic synergies between tau and TDP-43 as a new therapeutic strategy for AD with comorbid TDP-43 pathology.

scholarly journals Phosphoinositides signaling modulates microglial actin remodeling and phagocytosis in Alzheimer’s disease

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Smita Eknath Desale ◽  
Subashchandrabose Chinnathambi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Signaling Pathways ◽  
Amyloid Β ◽  
Dietary Fatty Acids ◽  
Receptor Expression ◽  
Actin Binding ◽  
Actin Remodeling ◽  
Protein Deposits

AbstractAlzheimer’s disease is one of the neurodegenerative diseases, characterized by the accumulation of abnormal protein deposits, which disrupts signal transduction in neurons and other glia cells. The pathological protein in neurodegenerative diseases, Tau and amyloid-β contribute to the disrupted microglial signaling pathways, actin cytoskeleton, and cellular receptor expression. The important secondary messenger lipids i.e., phosphatidylinositols are largely affected by protein deposits of amyloid-β in Alzheimer’s disease. Phosphatidylinositols are the product of different phosphatidylinositol kinases and the state of phosphorylation at D3, D4, and D5 positions of inositol ring. Phosphatidylinositol 3,4,5-triphosphate (PI 3, 4, 5-P3) involves in phagocytic cup formation, cell polarization, whereas Phosphatidylinositol 4,5-bisphosphate (PI 4, 5-P2)-mediates the process of phagosomes formation and further its fusion with early endosome.. The necessary activation of actin-binding proteins such as Rac, WAVE complex, and ARP2/3 complex for the actin polymerization in the process of phagocytosis, migration is regulated and maintained by PI 3, 4, 5-P3 and PI 4, 5-P2. The ratio and types of fatty acid intake can influence the intracellular secondary lipid messengers along with the cellular content of phaphatidylcholine and phosphatidylethanolamine. The Amyloid-β deposits and extracellular Tau seeds disrupt phosphatidylinositides level and actin cytoskeletal network that hamper microglial-signaling pathways in AD. We hypothesize that being a lipid species intracellular levels of phosphatidylinositol would be regulated by dietary fatty acids. Further we are interested to understand phosphoinositide-based signaling cascades in phagocytosis and actin remodeling.

scholarly journals Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease: Current Evidence and Future Perspectives

2021 ◽  
Vol 11 (2) ◽  
pp. 215
Author(s):  
Donovan A. McGrowder ◽  
Fabian Miller ◽  
Kurt Vaz ◽  
Chukwuemeka Nwokocha ◽  
Cameil Wilson-Clarke ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Late Onset ◽  
Amyloid Β ◽  
Current Evidence ◽  
Csf Biomarkers ◽  
Diagnostic Efficacy ◽  
Neurofilament Light ◽  
New Biomarkers

Alzheimer’s disease is a progressive, clinically heterogeneous, and particularly complex neurodegenerative disease characterized by a decline in cognition. Over the last two decades, there has been significant growth in the investigation of cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease. This review presents current evidence from many clinical neurochemical studies, with findings that attest to the efficacy of existing core CSF biomarkers such as total tau, phosphorylated tau, and amyloid-β (Aβ42), which diagnose Alzheimer’s disease in the early and dementia stages of the disorder. The heterogeneity of the pathophysiology of the late-onset disease warrants the growth of the Alzheimer’s disease CSF biomarker toolbox; more biomarkers showing other aspects of the disease mechanism are needed. This review focuses on new biomarkers that track Alzheimer’s disease pathology, such as those that assess neuronal injury (VILIP-1 and neurofilament light), neuroinflammation (sTREM2, YKL-40, osteopontin, GFAP, progranulin, and MCP-1), synaptic dysfunction (SNAP-25 and GAP-43), vascular dysregulation (hFABP), as well as CSF α-synuclein levels and TDP-43 pathology. Some of these biomarkers are promising candidates as they are specific and predict future rates of cognitive decline. Findings from the combinations of subclasses of new Alzheimer’s disease biomarkers that improve their diagnostic efficacy in detecting associated pathological changes are also presented.

Destabilization of Alzheimer’s Aβ42 protofibrils with acyclovir, carmustine, curcumin, and tetracycline: Insights from molecular dynamics simulations

2021 ◽  
Author(s):  
Ishrat Jahan ◽  
Shahid M Nayeem
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Neurodegenerative Diseases ◽  
Molecular Dynamics Simulations ◽  
Amyloid Β ◽  
Neural Tissue ◽  
Amyloid Β Peptide ◽  
Characteristic Symptom ◽  
Dynamics Simulations

One of the most common dementia among neurodegenerative diseases is Alzheimer’s disease (AD). The characteristic symptom of AD is the deposition and aggregation of amyloid-β-peptide in the neural tissue. A...

scholarly journals Dimensional Changes in Lipid Rafts from Human Brain Cortex Associated to Development of Alzheimer’s Disease. Predictions from an Agent-Based Mathematical Model

2021 ◽  
Vol 22 (22) ◽  
pp. 12181
Author(s):  
Guido Santos ◽  
Mario Díaz
Keyword(s):  
Alzheimer’S Disease ◽  
Mathematical Model ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Lipid Rafts ◽  
Brain Cortex ◽  
Clinical Symptoms ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Human Brain Cortex

Alzheimer’s disease (AD) is a neurodegenerative disease caused by abnormal functioning of critical physiological processes in nerve cells and aberrant accumulation of protein aggregates in the brain. The initial cause remains elusive—the only unquestionable risk factor for the most frequent variant of the disease is age. Lipid rafts are microdomains present in nerve cell membranes and they are known to play a significant role in the generation of hallmark proteinopathies associated to AD, namely senile plaques, formed by aggregates of amyloid β peptides. Recent studies have demonstrated that human brain cortex lipid rafts are altered during early neuropathological phases of AD as defined by Braak and Braak staging. The lipid composition and physical properties of these domains appear altered even before clinical symptoms are detected. Here, we use a coarse grain molecular dynamics mathematical model to predict the dimensional evolution of these domains using the experimental data reported by our group in human frontal cortex. The model predicts significant size and frequency changes which are detectable at the earliest neuropathological stage (ADI/II) of Alzheimer’s disease. Simulations reveal a lower number and a larger size in lipid rafts from ADV/VI, the most advanced stage of AD. Paralleling these changes, the predictions also indicate that non-rafts domains undergo simultaneous alterations in membrane peroxidability, which support a link between oxidative stress and AD progression. These synergistic changes in lipid rafts dimensions and non-rafts peroxidability are likely to become part of a positive feedback loop linked to an irreversible amyloid burden and neuronal death during the evolution of AD neuropathology.

Prions and Neurodegenerative Diseases: A Focus on Alzheimer’s Disease

2021 ◽  
pp. 1-16
Author(s):  
Alessio Crestini ◽  
Francesca Santilli ◽  
Stefano Martellucci ◽  
Elena Carbone ◽  
Maurizio Sorice ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Amyloid Β ◽  
Specific Protein ◽  
Cellular Prion Protein ◽  
Aβ Oligomers ◽  
The Central Nervous System ◽  
Induced Signal

Specific protein misfolding and aggregation are mechanisms underlying various neurodegenerative diseases such as prion disease and Alzheimer’s disease (AD). The misfolded proteins are involved in prions, amyloid-β (Aβ), tau, and α-synuclein disorders; they share common structural, biological, and biochemical characteristics, as well as similar mechanisms of aggregation and self-propagation. Pathological features of AD include the appearance of plaques consisting of deposition of protein Aβ and neurofibrillary tangles formed by the hyperphosphorylated tau protein. Although it is not clear how protein aggregation leads to AD, we are learning that the cellular prion protein (PrPC) plays an important role in the pathogenesis of AD. Herein, we first examined the pathogenesis of prion and AD with a focus on the contribution of PrPC to the development of AD. We analyzed the mechanisms that lead to the formation of a high affinity bond between Aβ oligomers (AβOs) and PrPC. Also, we studied the role of PrPC as an AβO receptor that initiates an AβO-induced signal cascade involving mGluR5, Fyn, Pyk2, and eEF2K linking Aβ and tau pathologies, resulting in the death of neurons in the central nervous system. Finally, we have described how the PrPC-AβOs interaction can be used as a new potential therapeutic target for the treatment of PrPC-dependent AD.

Genetic variability at the amyloid-β precursor protein locus may contribute to the risk of late-onset Alzheimer's disease

1999 ◽  
Vol 269 (2) ◽  
pp. 67-70 ◽  
Author(s):  
Fabienne Wavrant-De Vrièze ◽  
Richard Crook ◽  
Peter Holmans ◽  
Patrick Kehoe ◽  
Michael J. Owen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variability ◽  
Late Onset ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Protein Locus

scholarly journals PRECISION MEDICINE - THE GOLDEN GATE FOR DETECTION, TREATMENT AND PREVENTION OF ALZHEIMER’S DISEASE

2016 ◽  
pp. 1-17
Author(s):  
H. Hampel ◽  
S.E. O’Bryant ◽  
J.I. Castrillo ◽  
C. Ritchie ◽  
K. Rojkova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Precision Medicine ◽  
Molecular Mechanisms ◽  
Clinical Symptoms ◽  
Late Onset ◽  
Therapeutic Success ◽  
Preclinical Stage ◽  
Treatment And Prevention

During this decade, breakthrough conceptual shifts have commenced to emerge in the field of Alzheimer’s disease (AD) recognizing risk factors and the non-linear dynamic continuum of complex pathophysiologies amongst a wide dimensional spectrum of multi-factorial brain proteinopathies/neurodegenerative diseases. As is the case in most fields of medicine, substantial advancements in detecting, treating and preventing AD will likely evolve from the generation and implementation of a systematic precision medicine strategy. This approach will likely be based on the success found from more advanced research fields, such as oncology. Precision medicine will require integration and transfertilization across fragmented specialities of medicine and direct reintegration of Neuroscience, Neurology and Psychiatry into a continuum of medical sciences away from the silo approach. Precision medicine is biomarker-guided medicine on systems-levels that takes into account methodological advancements and discoveries of the comprehensive pathophysiological profiles of complex multi-factorial neurodegenerative diseases, such as late-onset sporadic AD. This will allow identifying and characterizing the disease processes at the asymptomatic preclinical stage, where pathophysiological and topographical abnormalities precede overt clinical symptoms by many years to decades. In this respect, the uncharted territory of the AD preclinical stage has become a major research challenge as the field postulates that early biomarker guided customized interventions may offer the best chance of therapeutic success. Clarification and practical operationalization is needed for comprehensive dissection and classification of interacting and converging disease mechanisms, description of genomic and epigenetic drivers, natural history trajectories through space and time, surrogate biomarkers and indicators of risk and progression, as well as considerations about the regulatory, ethical, political and societal consequences of early detection at asymptomatic stages. In this scenario, the integrated roles of genome sequencing, investigations of comprehensive fluid-based biomarkers and multimodal neuroimaging will be of key importance for the identification of distinct molecular mechanisms and signaling pathways in subsets of asymptomatic people at greatest risk for progression to clinical milestones due to those specific pathways. The precision medicine strategy facilitates a paradigm shift in Neuroscience and AD research and development away from the classical “one-size-fits-all” approach in drug discovery towards biomarker guided “molecularly” tailored therapy for truly effective treatment and prevention options. After the long and winding decade of failed therapy trials progress towards the holistic systems-based strategy of precision medicine may finally turn into the new age of scientific and medical success curbing the global AD epidemic.

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