Tau burden and the functional connectome in Alzheimer’s disease and progressive supranuclear palsy

Brain, Journal Year: 2017, Volume and Issue: 141(2), P. 550 - 567

Published: Nov. 30, 2017

Alzheimer's disease and progressive supranuclear palsy (PSP) represent neurodegenerative tauopathies with predominantly cortical versus subcortical burden. In disease, neuropathology atrophy preferentially affect 'hub' brain regions that are densely connected. It was unclear whether hubs differentially affected by neurodegeneration because they more likely to receive pathological proteins propagate trans-neuronally, in a prion-like manner, or selectively vulnerable due lack of local trophic factors, higher metabolic demands, differential gene expression. We assessed the relationship between tau burden functional connectivity, combining vivo PET imaging using ligand AV-1451, graph theoretic measures resting state MRI 17 patients PSP, 12 controls. Strongly connected nodes displayed pathology independently intrinsic connectivity network, validating predictions theories trans-neuronal spread but not supporting role for demands deficient support accumulation. This compensatory phenomenon, as consequence increasing weakening these same nodes, reducing weighted degree efficiency resulting weaker 'small-world' properties. Conversely, unlike those accrued were metric properties associated increased demand rather than strong connectivity. Together, findings go some way towards explaining why affects large scale networks throughout cortex while PSP is concentrated small number structures. Further, we demonstrate midbrain deep nuclei strengthened cortico-cortical Disrupted cortico-subcortical cortico-brainstem interactions meant information transfer took less direct paths, passing through larger closeness centrality eigenvector degree, clustering, betweenness efficiency. Our results have wide-ranging implications, from validation models trafficking humans understanding regional reorganization.

Language: Английский

---

Type 2 Diabetes Mellitus and Alzheimer’s Disease: Role of Insulin Signalling and Therapeutic Implications

International Journal of Molecular Sciences, Journal Year: 2018, Volume and Issue: 19(11), P. 3306 - 3306

Published: Oct. 24, 2018

In the last two decades, numerous in vitro studies demonstrated that insulin receptors and theirs downstream pathways are widely distributed throughout brain. This evidence has proven that; at variance with previous believes; insulin/insulin-like-growth-factor (IGF) signalling plays a crucial role regulation of different central nervous system (CNS) tasks. The most important these functions include: synaptic formation; neuronal plasticity; learning; memory; stem cell activation; neurite growth repair. Therefore; dysfunction levels metabolism can contribute to development number brain disorders. Growing evidences demonstrate close relationship between Type 2 Diabetes Mellitus (T2DM) neurodegenerative disorders such as Alzheimer’s disease. They, fact, share many pathophysiological characteristics comprising impaired sensitivity, amyloid β accumulation, tau hyper-phosphorylation, vasculopathy, inflammation oxidative stress. this article, we will review clinical experimental linking resistance, T2DM neurodegeneration, objective specifically focus on signalling-related mechanisms. We also evaluate pharmacological strategies targeting potential therapeutic tools patients cognitive impairment.

Language: Английский

---

A Brief Overview of Tauopathy: Causes, Consequences, and Therapeutic Strategies

Trends in Pharmacological Sciences, Journal Year: 2017, Volume and Issue: 38(7), P. 637 - 648

Published: April 26, 2017

Language: Английский

---

Elimination of substances from the brain parenchyma: efflux via perivascular pathways and via the blood–brain barrier

Fluids and Barriers of the CNS, Journal Year: 2018, Volume and Issue: 15(1)

Published: Oct. 19, 2018

This review considers efflux of substances from brain parenchyma quantified as values clearances (CL, stated in µL g−1 min−1). Total clearance a substance is the sum for all available routes including perivascular pathways and blood–brain barrier. Perivascular contributes to water-soluble substances. Substances leaving via may enter cerebrospinal fluid (CSF) or lymph. These are also involved entry CSF. However, evidence demonstrating net flow inwards along arteries then outwards veins (the glymphatic hypothesis) still lacking. CLperivascular, that routes, has been measured by following fate exogenously applied labelled tracer amounts sucrose, inulin serum albumin, which not metabolized eliminated across With these total CL ≅ 1 have measured. at least partly other i.e. barrier, higher values. crossing barrier do so passive, non-specific means with CLblood-brain ranging < 0.01 > 1000 water CO2. many small solutes predictable their oil/water partition molecular weight. Transporters specific glucose, lactate polar substrates facilitate producing 50. The principal route movement Na+ Cl− ions probably paracellular through tight junctions between endothelial cells ~ 1. There large fluxes amino acids into out but only observed suggesting substantial reuse essential α-ketoacids within brain. Amyloid-β efflux, measurably faster than inulin, primarily leaves this be important amyloid-β reaches arterial walls resulting cerebral amyloid angiopathy.

Language: Английский

---

Role of tau protein in Alzheimer's disease: The prime pathological player

International Journal of Biological Macromolecules, Journal Year: 2020, Volume and Issue: 163, P. 1599 - 1617

Published: Aug. 9, 2020

Language: Английский

---

Review of Current Strategies for Delivering Alzheimer’s Disease Drugs across the Blood-Brain Barrier

International Journal of Molecular Sciences, Journal Year: 2019, Volume and Issue: 20(2), P. 381 - 381

Published: Jan. 17, 2019

Effective therapy for Alzheimer’s disease is a major challenge in the pharmaceutical sciences. There are six FDA approved drugs (e.g., donepezil, memantine) that show some effectiveness; however, they only relieve symptoms. Two factors hamper research. First, cause of not fully understood. Second, blood-brain barrier restricts drug efficacy. This review summarized current knowledge relevant to both these factors. we reviewed pathophysiology disease. Next, structural and biological properties barrier. We then described most promising delivery systems have been developed recent years; include polymeric nanoparticles, liposomes, metallic nanoparticles cyclodextrins. Overall, aim provide ideas clues design effective penetrating treat

Language: Английский

---

Combined effects of scanning ultrasound and a tau-specific single chain antibody in a tau transgenic mouse model

Brain, Journal Year: 2017, Volume and Issue: 140(5), P. 1220 - 1230

Published: Feb. 21, 2017

Alzheimer's disease is characterized by the deposition of amyloid-β as extracellular plaques and hyperphosphorylated tau intracellular neurofibrillary tangles. Tau pathology characterizes not only disease, but also many other tauopathies, presenting an attractive therapeutic target. Passive immunotherapy has been previously explored; however, because a small fraction peripherally delivered antibodies crosses blood–brain barrier, enters brain engages with that forms aggregates, more efficient ways antibody delivery neuronal uptake are warranted. In brain, exists multiple isoforms. Here, we investigated efficacy novel 2N isoform-specific single chain fragment, RN2N, passive immunization in P301L human transgenic pR5 mouse model. We demonstrate that, treated mice, RN2N reduces anxiety-like behaviour phosphorylation at distinct sites. When administration was combined focused ultrasound scanning mode (scanning ultrasound), into neurons were markedly increased, significantly enhanced. Our study provides evidence viable tool to enhance biologics across barrier improve outcomes further presents single-chain alternative full-length antibodies.

Language: Английский

---

Effects ofin vivoconditions on amyloid aggregation

Chemical Society Reviews, Journal Year: 2019, Volume and Issue: 48(14), P. 3946 - 3996

Published: Jan. 1, 2019

One of the grand challenges biophysical chemistry is to understand principles that govern protein misfolding and aggregation, which a highly complex process sensitive initial conditions, operates on huge range length- timescales, has products from dimers macroscopic amyloid fibrils. Aberrant aggregation associated with more than 25 diseases, include Alzheimer's, Parkinson's, Huntington's, type II diabetes. Amyloid been extensively studied in test tube, therefore under conditions are far physiological relevance. Hence, there dire need extend these investigations vivo where formation affected by myriad biochemical interactions. As hallmark neurodegenerative interactions be understood detail develop novel therapeutic interventions, as millions people globally suffer disorders The aim this review document progress research physicochemical perspective special focus factors influencing amyloid-β peptide, islet polypeptide, α-synuclein, hungingtin protein.

Language: Английский

---

Amyloid β, Tau, and α-Synuclein aggregates in the pathogenesis, prognosis, and therapeutics for neurodegenerative diseases

Progress in Neurobiology, Journal Year: 2022, Volume and Issue: 214, P. 102270 - 102270

Published: April 18, 2022

Aggregation of specific proteins are histopathological hallmarks several neurodegenerative diseases, such as, Amyloid β (Aβ) plaques and tau neurofibrillary tangles in Alzheimer's disease (AD); morphologically different inclusions ratiometric 3 repeat (3 R) 4 (4 isoforms progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's (PiD); α-Synuclein (α-Syn) containing Lewy bodies (LBs) dystrophic neurites (LNs) Parkinson's (PD) dementia with (DLB). However, mixed brain protein pathologies have been frequently observed many these diseases normal aging brains, among which Aβ/tau tau/α-Syn crosstalks received increased attention. Interestingly, studies also shown synergistic interplay Aβ, tau, α-Syn suggesting a triumvirate. In this review, we summarize the emerging evidence aggregation pathophysiology, their overlap spectrum including AD, PSP, PiD, CBD, PD DLB. We discuss prognostic advancements made biomarker imaging techniques triumvirate proteinopathies. Finally, combined therapeutic modality involving biomarkers for future combinatorial immunotherapeutic targeting more than one aggregates. hope that multitarget approach will or additive effects to manage two might uncover promising strategy personalized combination therapies. Managing by optimizing diagnostic criteria correct immunotherapies be key factor success treatment.

Language: Английский

---

Mitochondrial Dysfunction as a Driver of Cognitive Impairment in Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(9), P. 4850 - 4850

Published: May 3, 2021

Alzheimer's disease (AD) is the most frequent cause of age-related neurodegeneration and cognitive impairment, there are currently no broadly effective therapies. The underlying pathogenesis complex, but a growing body evidence implicates mitochondrial dysfunction as common pathomechanism involved in many hallmark features AD brain, such formation amyloid-beta (Aβ) aggregates (amyloid plaques), neurofibrillary tangles, cholinergic system dysfunction, impaired synaptic transmission plasticity, oxidative stress, neuroinflammation, that lead to dysfunction. Indeed, concomitant with progressive accumulation Aβ an early event pathogenesis. Healthy mitochondria critical for providing sufficient energy maintain endogenous neuroprotective reparative mechanisms, while disturbances function, motility, fission, fusion neuronal malfunction degeneration associated excess free radical production reduced intracellular calcium buffering. In addition, can contribute amyloid-β precursor protein (APP) expression misprocessing produce pathogenic fragments (e.g., Aβ1-40). Given this background, we present overview importance maintenance function how acts driver impairment AD. Additionally, provide brief summary possible treatments targeting therapeutic approaches

Language: Английский

---