Synergy between amyloid-β and tau in Alzheimer’s disease

Nature Neuroscience, Год журнала: 2020, Номер 23(10), С. 1183 - 1193

Опубликована: Авг. 10, 2020

Язык: Английский

---

A Review of the Common Neurodegenerative Disorders: Current Therapeutic Approaches and the Potential Role of Nanotherapeutics

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(3), С. 1851 - 1851

Опубликована: Фев. 6, 2022

Neurodegenerative disorders are primarily characterized by neuron loss. The most common neurodegenerative include Alzheimer’s and Parkinson’s disease. Although there several medicines currently approved for managing disorders, a large majority of them only help with associated symptoms. This lack pathogenesis-targeting therapies is due to the restrictive effects blood–brain barrier (BBB), which keeps close 99% all “foreign substances” out brain. Since their discovery, nanoparticles have been successfully used targeted delivery into many organs, including review briefly describes pathophysiology Alzheimer’s, disease, amyotrophic lateral sclerosis, current management approaches. We then highlight major challenges brain-drug delivery, followed role nanotherapeutics diagnosis treatment various neurological disorders.

Язык: Английский

---

Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Июнь 30, 2023

Abstract Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer’s disease (AD), and its accumulation has been considered as molecular driver pathogenesis progression. Aβ prime target for development AD therapy. However, repeated failures Aβ-targeted clinical trials have cast considerable doubt on amyloid cascade hypothesis whether drug followed correct course. recent successes targeted assuaged those doubts. In this review, we discussed evolution over last 30 years summarized application diagnosis modification. particular, extensively pitfalls, promises important unanswered questions regarding current anti-Aβ therapy, well strategies further study more feasible approaches optimization prevention treatment.

Язык: Английский

---

The physiological roles of tau and Aβ: implications for Alzheimer’s disease pathology and therapeutics

Acta Neuropathologica, Год журнала: 2020, Номер 140(4), С. 417 - 447

Опубликована: Июль 29, 2020

Abstract Tau and amyloid beta (Aβ) are the prime suspects for driving pathology in Alzheimer’s disease (AD) and, as such, have become focus of therapeutic development. Recent research, however, shows that these proteins been highly conserved throughout evolution may crucial, physiological roles. Such functions be lost during AD progression or unintentionally disrupted by tau- Aβ-targeting therapies. has revealed to more than a simple stabiliser microtubules, reported play role range biological processes including myelination, glucose metabolism, axonal transport, microtubule dynamics, iron homeostasis, neurogenesis, motor function, learning memory, neuronal excitability, DNA protection. Aβ is similarly multifunctional, proposed regulate angiogenesis, repair leaks blood–brain barrier, promote recovery from injury, act an antimicrobial peptide tumour suppressor. This review will discuss potential roles tau Aβ, highlighting how changes contribute pathology, well implications We propose balanced consideration both pathological essential design safe effective therapeutics.

Язык: Английский

---

Synaptic degeneration in Alzheimer disease

Nature Reviews Neurology, Год журнала: 2022, Номер 19(1), С. 19 - 38

Опубликована: Дек. 13, 2022

Язык: Английский

---

Biological aging processes underlying cognitive decline and neurodegenerative disease

Journal of Clinical Investigation, Год журнала: 2022, Номер 132(10)

Опубликована: Май 15, 2022

Alzheimer's disease and related dementias (ADRD) are among the top contributors to disability mortality in later life. As with many chronic conditions, aging is single most influential factor development of ADRD. Even older adults who remain free dementia throughout their lives, cognitive decline neurodegenerative changes appreciable advancing age, suggesting shared pathophysiological mechanisms. In this Review, we provide an overview cognition, brain morphology, neuropathological protein accumulation across lifespan humans, complementary mechanistic evidence from animal models. Next, highlight selected processes that differentially regulated disease, including aberrant autophagy, mitochondrial dysfunction, cellular senescence, epigenetic changes, cerebrovascular inflammation, lipid dysregulation. We summarize research clinical translational studies link biological underlying ADRD pathogenesis. Targeting fundamental may represent a yet relatively unexplored avenue attenuate both age-related Collaboration fields geroscience neuroscience, coupled new models more closely align human processes, necessary advance novel therapeutic discovery realm.

Язык: Английский

---

Amyloid-beta peptide and tau protein crosstalk in Alzheimer’s disease

Neural Regeneration Research, Год журнала: 2021, Номер 17(8), С. 1666 - 1666

Опубликована: Дек. 10, 2021

Alzheimer's disease is a neurodegenerative that accounts for most of the 50-million dementia cases worldwide in 2018. A large amount evidence supports amyloid cascade hypothesis, which states amyloid-beta accumulation triggers tau hyperphosphorylation and aggregation form neurofibrillary tangles, these aggregates lead to inflammation, synaptic impairment, neuronal loss, thus cognitive decline behavioral abnormalities. The poor correlation found between plaques, have led scientific community question whether actually triggering neurodegeneration disease. occurrence tangles better correlates loss clinical symptoms and, although may initiate events, impairment likely effector molecule neurodegeneration. Recently, it has been shown cooperatively work impair transcription genes involved function more importantly, downregulation partially reverses transcriptional perturbations. Despite mounting points an interplay tau, some factors could independently affect both pathologies. Thus, dual pathway there are common upstream causing abnormalities proposed. Among others, immune system seems be strongly Other factors, as apolipoprotein E ε4 isoform suggested act link hyperphosphorylation. Interestingly, amyloid-beta-immunotherapy reduces not only but also levels animal models trials. Likewise, tau-immunotherapy levels. even though immunotherapy advanced than tau-immunotherapy, combined tau-directed therapies at early stages recently proposed strategy stop progression

Язык: Английский

---

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

Progress in Neurobiology, Год журнала: 2022, Номер 214, С. 102270 - 102270

Опубликована: Апрель 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.

Язык: Английский

---

Reactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Янв. 10, 2022

Abstract Alzheimer’s disease (AD) alters astrocytes, but the effect of Aß and Tau pathology is poorly understood. TRAP-seq translatome analysis astrocytes in APP/PS1 ß-amyloidopathy MAPT P301S tauopathy mice revealed that only influenced expression AD risk genes, both pathologies precociously induced age-dependent changes, had distinct overlapping signatures found human post-mortem astrocytes. Both an astrocyte signature involving repression bioenergetic translation machinery, induction inflammation pathways plus protein degradation/proteostasis latter enriched targets inflammatory mediator Spi1 stress-activated cytoprotective Nrf2. Astrocyte-specific Nrf2 a reactive phenotype which recapitulated elements this proteostasis signature, reduced deposition phospho-tau accumulation their respective models, rescued brain-wide transcriptional deregulation, cellular pathology, neurodegeneration behavioural/cognitive deficits. Thus, induce profiles associated with deleterious adaptive-protective signals, can slow patho-progression.

Язык: Английский

---

Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease

Nature Aging, Год журнала: 2021, Номер 1(12), С. 1175 - 1188

Опубликована: Дек. 6, 2021

Язык: Английский

---