Tau and neuroinflammation: What impact for Alzheimer's Disease and Tauopathies?

Biomedical Journal, Journal Year: 2018, Volume and Issue: 41(1), P. 21 - 33

Published: Feb. 1, 2018

Alzheimer's Disease (AD) is a chronic neurodegenerative disorder and the most common type of dementia (60–80% cases). In 2016, nearly 44 million people were affected by AD or related dementia. characterized progressive neuronal damages leading to subtle latter obvious decline in cognitive functions including symptoms such as memory loss confusion, which ultimately require full-time medical care. Its neuropathology defined extracellular accumulation amyloid-β (Aβ) peptide into amyloid plaques, intraneuronal neurofibrillary tangles (NFT) consisting aggregated hyper- abnormal phosphorylation tau protein. The latter, identified also Tau pathology, observed broad spectrum neurological diseases commonly referred "Tauopathies". Besides these lesions, sustained neuroinflammatory processes occur, involving notably micro- astro-glial activation, contribute disease progression. Recent findings from genome wide association studies further support an instrumental role neuroinflammation. While interconnections existing between this innate immune response pathogenesis are widely described complex, elaborated evolving, only few focused on pathology. An adaptive takes place conjointly during course, indicated presence vascular parenchymal T-cell patients' brain. underlying mechanisms infiltration its consequences with regards pathology remain understudied so far. present review, we highlight interplays innate/adaptive responses.

Language: Английский

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Locus coeruleus imaging as a biomarker for noradrenergic dysfunction in neurodegenerative diseases

Brain, Journal Year: 2019, Volume and Issue: 142(9), P. 2558 - 2571

Published: June 11, 2019

Abstract Pathological alterations to the locus coeruleus, major source of noradrenaline in brain, are histologically evident early stages neurodegenerative diseases. Novel MRI approaches now provide an opportunity quantify structural features coeruleus vivo during disease progression. In combination with neuropathological biomarkers, imaging could help understand contribution neurodegeneration clinical and pathological manifestations Alzheimer’s disease, atypical dementias Parkinson’s disease. Moreover, as functional sensitivity noradrenergic system is likely change progression, measures integrity new pathophysiological insights into cognitive behavioural symptoms. Locus also holds promise stratify patients trials according dysfunction. this article, we present a consensus on how non-invasive assessment can be used for research We outline next steps vivo, post-mortem studies that lay groundwork evaluate potential biomarker

Language: Английский

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Long Road to Ruin: Noradrenergic Dysfunction in Neurodegenerative Disease

Trends in Neurosciences, Journal Year: 2018, Volume and Issue: 41(4), P. 211 - 223

Published: Feb. 20, 2018

Language: Английский

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Past, present and future of therapeutic strategies against amyloid-β peptides in Alzheimer’s disease: a systematic review

Ageing Research Reviews, Journal Year: 2021, Volume and Issue: 72, P. 101496 - 101496

Published: Oct. 22, 2021

Alzheimer's disease (AD) is the most prevalent neurodegenerative in ageing, affecting around 46 million people worldwide but few treatments are currently available. The etiology of AD still puzzling, and new drugs development clinical trials have high failure rates. Urgent outline an integral (multi-target) effective treatment needed. Accumulation amyloid-β (Aβ) peptides considered one fundamental neuropathological pillars disease, its dyshomeostasis has shown a crucial role onset. Therefore, many amyloid-targeted therapies been investigated. Here, we will systematically review recent (from 2014) investigational, follow-up studies focused on anti-amyloid strategies to summarize analyze their current potential. Combination anti-Aβ with developing early detection biomarkers other therapeutic agents acting functional changes be highlighted this review. Near-term approval seems likely for several against Aβ, FDA monoclonal oligomers antibody –aducanumab– raising hopes controversies. We conclude that, oligomer-epitope specific Aβ implementation multiple improved risk prediction methods allowing detection, together factors such as hyperexcitability AD, could key slowing global pandemic.

Language: Английский

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Noradrenergic Modulation of Cognition in Health and Disease

Neural Plasticity, Journal Year: 2017, Volume and Issue: 2017, P. 1 - 14

Published: Jan. 1, 2017

Norepinephrine released by the locus coeruleus modulates cellular processes and synaptic transmission in central nervous system through its actions at a number of pre- postsynaptic receptors. This transmitter facilitates sensory signal detection promotes waking arousal, which are necessary for navigating complex dynamic environment. In addition to effects on processing behavior, norepinephrine is now recognized as contributor various aspects cognition, including attention, behavioral flexibility, working memory, long-term mnemonic processes. Two areas dense noradrenergic innervation, prefrontal cortex hippocampus, particularly important with regard these functions. Due role mediating normal cognitive function, it reasonable expect that becomes dysfunctional neuropsychiatric neurodegenerative diseases characterized deficits. this review, we summarize unique plays cortical hippocampal function how interaction receptors contributes behaviors. We further assess changes occur Alzheimer’s disease, Parkinson’s attention-deficit/hyperactivity disorder, schizophrenia contribute decline pathologies.

Language: Английский

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Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer’s disease

Brain, Journal Year: 2017, Volume and Issue: 140(11), P. 3023 - 3038

Published: Aug. 22, 2017

See Grinberg and Heinsen (doi:10.1093/brain/awx261) for a scientific commentary on this article. Clinical evidence suggests that aberrant tau accumulation in the locus coeruleus noradrenergic dysfunction may be critical early step Alzheimer's disease progression. Yet, an accurate preclinical model of these phenotypes includes pretangle accrual coeruleus, loss innervation deficits coeruleus/norepinephrine modulated behaviours, does not exist, hampering identification underlying mechanisms development coeruleus-based therapies. Here, transgenic rat (TgF344-AD) expressing disease-causing mutant amyloid precursor protein (APPsw) presenilin-1 (PS1ΔE9) was characterized histological behavioural signs reminiscent mild cognitive impairment/early disease. In TgF344-AD rats, hyperphosphorylated detected prior to medial entorhinal cortex or hippocampus, pathology negatively correlated with cortex. Likewise, rats displayed progressive hippocampal norepinephrine levels fibres dentate gyrus, no frank cell body loss. Cultured mouse neurons hyperphosphorylation-prone human had shorter neurites than control neurons, but similar viability, suggesting causal link between altered fibre morphology. impaired reversal learning Morris water maze compared their wild-type littermates, which rescued by chemogenetic activation via designer receptors exclusively activated drugs (DREADDs). Our results indicate uniquely meet several key criteria suitable progression, suggest substantial window opportunity coeruleus/ norepinephrine-based therapeutics exists.

Language: Английский

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The role of the locus coeruleus in the generation of pathological anxiety

Brain and Neuroscience Advances, Journal Year: 2020, Volume and Issue: 4, P. 239821282093032 - 239821282093032

Published: Jan. 1, 2020

This review aims to synthesise a large pre-clinical and clinical literature related hypothesised role of the locus coeruleus norepinephrine system in responses acute chronic threat, as well emergence pathological anxiety. The has widespread projections throughout central nervous system, which act globally modulate arousal states adaptive behavior, crucially positioned play significant modulating both ascending visceral descending cortical neurocognitive information. In response threat or stressor, coeruleus–norepinephrine modulates arousal, alerting orienting functions can have powerful effect on regulation multiple memory systems. Chronic stress leads amplification reactivity subsequent stressors, is coupled with anxiety-like behaviors rodents. While direct vivo evidence for dysfunction humans anxiety remains limited, recent advances high-resolution 7-T magnetic resonance imaging computational modeling approaches are starting provide new insights into characteristics.

Language: Английский

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The role of noradrenaline in cognition and cognitive disorders

Brain, Journal Year: 2021, Volume and Issue: 144(8), P. 2243 - 2256

Published: March 11, 2021

Abstract Many aspects of cognition and behaviour are regulated by noradrenergic projections to the forebrain originating from locus coeruleus, acting through alpha beta adrenoreceptors. Loss these is common in neurodegenerative diseases contributes their cognitive behavioural deficits. We review evidence for a modulation its contribution Alzheimer’s disease, Parkinson’s disease other disorders. discuss advances human imaging computational methods that quantify coeruleus function humans, highlight potential new treatment strategies.

Language: Английский

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The mechanistic link between selective vulnerability of the locus coeruleus and neurodegeneration in Alzheimer’s disease

Acta Neuropathologica, Journal Year: 2021, Volume and Issue: 141(5), P. 631 - 650

Published: Jan. 11, 2021

Abstract Alzheimer’s disease (AD) is neuropathologically characterized by the intracellular accumulation of hyperphosphorylated tau and extracellular deposition amyloid-β plaques, which affect certain brain regions in a progressive manner. The locus coeruleus (LC), small nucleus pons brainstem, widely recognized as one earliest sites neurofibrillary tangle formation AD. Patients with AD exhibit significant neuronal loss LC, resulting marked reduction its size function. vastly innervates several brain, primary source neurotransmitter norepinephrine (NE) central nervous system. Considering that NE major modulator behavior, contributing to neuroprotection suppression neuroinflammation, degeneration LC ultimate dysregulation LC–NE system has detrimental effects brain. In this review, we detail neuroanatomy function essential role neuroprotection, how dysregulated We discuss AD-related neuropathologic changes mechanisms neurons are selectively vulnerable insult. Further, elucidate neurotoxic de-innervation both locally at projection sites, augments pathology, progression severity. summarize preservation could be used treatment other neurodegenerative diseases affected degeneration.

Language: Английский

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The Cholinergic System, the Adrenergic System and the Neuropathology of Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(3), P. 1273 - 1273

Published: Jan. 28, 2021

Neurodegenerative diseases are a major public health problem worldwide with wide spectrum of symptoms and physiological effects. It has been long reported that the dysregulation cholinergic system adrenergic linked to etiology Alzheimer's disease. Cholinergic neurons widely distributed in brain regions play role cognitive functions normal signaling related learning memory is dependent on acetylcholine. The Locus Coeruleus norepinephrine (LC-NE) main noradrenergic nucleus projects supplies different regions. Norepinephrine shown be neuroprotective against neurodegeneration plays behavior cognition. dysregulated degeneration basalis Meynert basal forebrain LC-NE were aim this review describe current literature pathology disease potential therapeutic implications.

Language: Английский

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