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 Neuronal heparan sulfates promote amyloid pathology by modulating brain amyloid-β clearance and aggregation in Alzheimer’s disease

2016 ◽  
Vol 8 (332) ◽  
pp. 332ra44-332ra44 ◽  
Author(s):  
Chia-Chen Liu ◽  
Na Zhao ◽  
Yu Yamaguchi ◽  
John R. Cirrito ◽  
Takahisa Kanekiyo ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Therapeutic Interventions ◽  
Postmortem Human Brain ◽  
Aβ Clearance ◽  
Heparan Sulfates ◽  
The Brain

Accumulation of amyloid-β (Aβ) peptide in the brain is the first critical step in the pathogenesis of Alzheimer’s disease (AD). Studies in humans suggest that Aβ clearance from the brain is frequently impaired in late-onset AD. Aβ accumulation leads to the formation of Aβ aggregates, which injure synapses and contribute to eventual neurodegeneration. Cell surface heparan sulfates (HSs), expressed on all cell types including neurons, have been implicated in several features in the pathogenesis of AD including its colocalization with amyloid plaques and modulatory role in Aβ aggregation. We show that removal of neuronal HS by conditional deletion of the Ext1 gene, which encodes an essential glycosyltransferase for HS biosynthesis, in postnatal neurons of amyloid model APP/PS1 mice led to a reduction in both Aβ oligomerization and the deposition of amyloid plaques. In vivo microdialysis experiments also detected an accelerated rate of Aβ clearance in the brain interstitial fluid, suggesting that neuronal HS either inhibited or represented an inefficient pathway for Aβ clearance. We found that the amounts of various HS proteoglycans (HSPGs) were increased in postmortem human brain tissues from AD patients, suggesting that this pathway may contribute directly to amyloid pathogenesis. Our findings have implications for AD pathogenesis and provide insight into therapeutic interventions targeting Aβ-HSPG interactions.

scholarly journals Transcriptome analysis of a protein-truncating mutation in sortilin-related receptor 1 associated with early-onset familial Alzheimer’s disease indicates effects on mitochondrial and ribosome function in young-adult zebrafish brains

2020 ◽  
Author(s):  
Karissa Barthelson ◽  
Stephen Pederson ◽  
Morgan Newman ◽  
Michael Lardelli
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Onset ◽  
Reverse Genetics ◽  
Late Onset ◽  
Model Organism ◽  
Amyloid Β ◽  
Targeted Mutagenesis ◽  
Receptor Protein ◽  
Truncating Mutation

AbstractThe early cellular stresses which eventually lead to Alzheimer’s disease (AD) remain poorly understood because we cannot access living, asymptomatic human AD brains for detailed molecular analyses. Sortilin-related receptor 1 (SORL1) encodes a multi-domain receptor protein genetically associated with both rare, early-onset familial AD (EOfAD) and common, sporadic late-onset AD (LOAD). SORL1 has been shown to play a role in the trafficking of the amyloid β A4 precursor protein (APP) which is cleaved proteolytically to form one of the pathological hallmarks of AD, amyloid β (Aβ) peptide. However, the other functions of SORL1 are less well understood. Here, we employed a reverse genetics approach to characterise the effect of an EOfAD mutation in SORL1 using zebrafish as a model organism. We performed targeted mutagenesis to generate an EOfAD-like mutation in the zebrafish orthologue of SORL1, and performed RNA-sequencing on mRNA isolated from a family of fish either heterozygous for the EOfAD-like mutation or their wild type siblings and identified subtle effects on the expression of genes which likely indicate changes in mitochondrial and ribosomal function. These changes appear to be independent of changes to expression of APP-related proteins in zebrafish, and mitochondrial content.

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.

Measuring Disease Modification in Alzheimer's Disease

CNS Spectrums ◽  
2007 ◽  
Vol 12 (S1) ◽  
pp. 11-14
Author(s):  
Jeffrey L. Cummings
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immunoglobulin A ◽  
Disease Process ◽  
Underlying Disease ◽  
Therapeutic Interventions ◽  
Disease Modification ◽  
Amyloid Disease ◽  
Therapeutic Modalities ◽  
Disease Modifying

AbstractWe appear to be on the brink of a new epoch of treatment for Alzheimer's disease. Compelling evidence suggests that Aβ42 secretion is the triggering event in the pathogenesis of Alzheimer's disease, and that tau aggregation may be an important secondary event linked to neurodegeneration. Prophylactic administration of anti-amyloid agents designed to prevent Aβ accumulation in persons with subclinical disease is likely to be more effective than therapeutic interventions in established Alzheimer's disease. Drug development programs in Alzheimer's disease focus primarily on agents with anti-amyloid disease-modifying properties, and many different pharmacologic approaches to reducing amyloid pathology and tauopathy are being studied. Classes of therapeutic modalities currently in advanced-stage clinical trial testing include forms of immunotherapy (active β -amyloid immunoconjugate and human intravenous immunoglobulin), a γ-secretase inhibitor, the selective Aβ42-lowering agent R-flurbiprofen, and the anti-aggregation agent tramiprosate. Non-traditional dementia therapies such as the HMG-CoA reductase inhibitors (statins), valproate, and lithium are now being assessed for clinical benefit as anti-amyloid disease-modifying treatments. Positive findings of efficacy and safety from clinical studies are necessary but not sufficient to demonstrate that a drug has disease-modifying properties. Definitive proof of disease-modification requires evidence from validated animal models of Alzheimer's disease; rigorously controlled clinical trials showing a significantly improved, stabilized, or slowed rate of decline in cognitive and global function compared to placebo; and prospectively obtained evidence from surrogate biomarkers that the treatment resulted in measurable biological changes associated with the underlying disease process.

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.

scholarly journals Elevated Expression of MiR-17 in Microglia of Alzheimer’s Disease Patients Abrogates Autophagy-Mediated Amyloid-β Degradation

2021 ◽  
Vol 12 ◽  
Author(s):  
Shady Estfanous ◽  
Kylene P. Daily ◽  
Mostafa Eltobgy ◽  
Nicholas P. Deems ◽  
Midhun N. K. Anne ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Therapeutic Interventions ◽  
Tissue Sections ◽  
Cargo Receptor ◽  
5Xfad Mouse ◽  
Aβ Degradation

Autophagy is a proposed route of amyloid-β (Aβ) clearance by microglia that is halted in Alzheimer’s Disease (AD), though mechanisms underlying this dysfunction remain elusive. Here, primary microglia from adult AD (5xFAD) mice were utilized to demonstrate that 5xFAD microglia fail to degrade Aβ and express low levels of autophagy cargo receptor NBR1. In 5xFAD mouse brains, we show for the first time that AD microglia express elevated levels of microRNA cluster Mirc1/Mir17-92a, which is known to downregulate autophagy proteins. By in situ hybridization in post-mortem AD human tissue sections, we observed that the Mirc1/Mir17-92a cluster member miR-17 is also elevated in human AD microglia, specifically in the vicinity of Aβ deposits, compared to non-disease controls. We show that NBR1 expression is negatively correlated with expression of miR-17 in human AD microglia via immunohistopathologic staining in human AD brain tissue sections. We demonstrate in healthy microglia that autophagy cargo receptor NBR1 is required for Aβ degradation. Inhibiting elevated miR-17 in 5xFAD mouse microglia improves Aβ degradation, autophagy, and NBR1 puncta formation in vitro and improves NBR1 expression in vivo. These findings offer a mechanism behind dysfunctional autophagy in AD microglia which may be useful for therapeutic interventions aiming to improve autophagy function in 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

Introduction: Amyloid-Based Interventions in Alzheimer's Disease

CNS Spectrums ◽  
2007 ◽  
Vol 12 (S1) ◽  
pp. 2-3 ◽  
Author(s):  
Gary J. Kennedy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immunoglobulin A ◽  
Disease Process ◽  
Underlying Disease ◽  
Therapeutic Interventions ◽  
Amyloid Disease ◽  
Therapeutic Modalities ◽  
Reductase Inhibitors ◽  
Disease Modifying

AbstractWe appear to be on the brink of a new epoch of treatment for Alzheimer's disease. Compelling evidence suggests that Aβ secretion is the triggering event in the pathogenesis of Alzheimer's disease, and that tau aggregation may be an important secondary event linked to neurodegeneration. Prophylactic administration of anti-amyloid agents designed to prevent Aβ accumulation in persons with subclinical disease is likely to be more effective than therapeutic interventions in established Alzheimer's disease. Drug development programs in Alzheimer's disease focus primarily on agents with anti-amyloid disease-modifying properties, and many different pharmacologic approaches to reducing amyloid pathology and tauopathy are being studied. Classes of therapeutic modalities currently in advanced-stage clinical trial testing include forms of immunotherapy (active β-amyloid immunoconjugate and human intravenous immunoglobulin), a γ-secretase inhibitor, the selective Aβ42-lowering agent R-flurbiprofen, and the anti-aggregation agent tramiprosate. Non-traditional dementia therapies such as the HMG-CoA reductase inhibitors (statins), valproate, and lithium are now being assessed for clinical benefit as anti-amyloid disease-modifying treatments. Positive findings of efficacy and safety from clinical studies are necessary but not sufficient to demonstrate that a drug has disease-modifying properties. Definitive proof of disease-modification requires evidence from validated animal models of Alzheimer's disease; rigorously controlled clinical trials showing a significantly improved, stabilized, or slowed rate of decline in cognitive and global function compared to placebo; and prospectively obtained evidence from surrogate biomarkers that the treatment resulted in measurable biological changes associated with the underlying disease process.

Poor Diet, Stress, and Inactivity Converge to Form a “Perfect Storm” That Drives Alzheimer’s Disease Pathogenesis

2019 ◽  
Vol 19 (2) ◽  
pp. 60-77 ◽  
Author(s):  
Anthony G. Pacholko ◽  
Caitlin A. Wotton ◽  
Lane K. Bekar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Environmental Factors ◽  
Late Onset ◽  
Caloric Intake ◽  
Amyloid Β ◽  
Tau Proteins ◽  
Loss Of Function ◽  
Brain Insulin Resistance ◽  
Perfect Storm

North American incidence of Alzheimer’s disease (AD) is expected to more than double over the coming generation. Although genetic factors surrounding the production and clearance of amyloid-β and phosphorylated tau proteins are known to be responsible for a subset of early-onset AD cases, they do not explain the pathogenesis of the far more prevalent sporadic late-onset variant of the disease. It is thus likely that lifestyle and environmental factors contribute to neurodegenerative processes implicated in the pathogenesis of AD. Herein, we review evidence that (1) excess sucrose consumption induces AD-associated liver pathologies and brain insulin resistance, (2) chronic stress overdrives activity of locus coeruleus neurons, leading to loss of function (a common event in neurodegeneration), (3) high-sugar diets and stress promote the loss of neuroprotective sex hormones in men and women, and (4) Western dietary trends set the stage for a lithium-deficient state. We propose that these factors may intersect as part of a “perfect storm” to contribute to the widespread prevalence of neurodegeneration and AD. In addition, we put forth the argument that exercise and supplementation with trace lithium can counteract many of the deleterious consequences associated with excessive caloric intake and perpetual stress. We conclude that lifestyle and environmental factors likely contribute to AD pathogenesis and that simple lifestyle and dietary changes can help counteract their effects.

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