scholarly journals Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression

2013 ◽  
Vol 4 (1) ◽  
Author(s):  
Dan Frenkel ◽  
Kim Wilkinson ◽  
Lingzhi Zhao ◽  
Suzanne E. Hickman ◽  
Terry K. Means ◽  
...  
Keyword(s):  
Disease Progression ◽  
Amyloid Β ◽  
Mononuclear Phagocytes

scholarly journals Application of optogenetic Amyloid-β distinguishes between metabolic and physical damages in neurodegeneration

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Chu Hsien Lim ◽  
Prameet Kaur ◽  
Emelyne Teo ◽  
Vanessa Yuk Man Lam ◽  
Fangchen Zhu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Biological Effects ◽  
Amyloid Β ◽  
Tissue Loss ◽  
Amyloid Β Peptide ◽  
Physical Damage ◽  
Living Tissues

The brains of Alzheimer’s disease patients show a decrease in brain mass and a preponderance of extracellular Amyloid-β plaques. These plaques are formed by aggregation of polypeptides that are derived from the Amyloid Precursor Protein (APP). Amyloid-β plaques are thought to play either a direct or an indirect role in disease progression, however the exact role of aggregation and plaque formation in the aetiology of Alzheimer’s disease (AD) is subject to debate as the biological effects of soluble and aggregated Amyloid-β peptides are difficult to separate in vivo. To investigate the consequences of formation of Amyloid-β oligomers in living tissues, we developed a fluorescently tagged, optogenetic Amyloid-β peptide that oligomerizes rapidly in the presence of blue light. We applied this system to the crucial question of how intracellular Amyloid-β oligomers underlie the pathologies of A. We use Drosophila, C. elegans and D. rerio to show that, although both expression and induced oligomerization of Amyloid-β were detrimental to lifespan and healthspan, we were able to separate the metabolic and physical damage caused by light-induced Amyloid-β oligomerization from Amyloid-β expression alone. The physical damage caused by Amyloid-β oligomers also recapitulated the catastrophic tissue loss that is a hallmark of late AD. We show that the lifespan deficit induced by Amyloid-β oligomers was reduced with Li+ treatment. Our results present the first model to separate different aspects of disease progression.

Cortisol, Amyloid-β, and Reserve Predicts Alzheimer’s Disease Progression for Cognitively Normal Older Adults

2019 ◽  
Vol 70 (2) ◽  
pp. 553-562 ◽  
Author(s):  
Chinedu T. Udeh-Momoh ◽  
Bowen Su ◽  
Stephanie Evans ◽  
Bang Zheng ◽  
Shireen Sindi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Amyloid Β ◽  
Cognitively Normal

scholarly journals Cytokine-Mediated Inhibition of Fibrillar Amyloid-β Peptide Degradation by Human Mononuclear Phagocytes

2008 ◽  
Vol 181 (6) ◽  
pp. 3877-3886 ◽  
Author(s):  
Masaru Yamamoto ◽  
Tomomi Kiyota ◽  
Shannon M. Walsh ◽  
Jianuo Liu ◽  
Jonathan Kipnis ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Mononuclear Phagocytes ◽  
Amyloid Β Peptide ◽  
Peptide Degradation

scholarly journals Amyloid β–associated cognitive decline in the absence of clinical disease progression and systemic illness

2017 ◽  
Vol 8 (1) ◽  
pp. 156-164 ◽  
Author(s):  
Karra D. Harrington ◽  
Yen Ying Lim ◽  
David Ames ◽  
Jason Hassenstab ◽  
Simon M. Laws ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Disease Progression ◽  
Amyloid Β ◽  
Clinical Disease ◽  
Clinical Disease Progression

scholarly journals Astrocyte-neuron interplay is critical for Alzheimer’s disease pathogenesis and is rescued by TRPA1 channel blockade

2021 ◽  
Author(s):  
Adrien Paumier ◽  
Sylvie Boisseau ◽  
Karin Pernet-Gallay ◽  
Alain Buisson ◽  
Mireille Albrieux
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Disease Progression ◽  
Spatial Working Memory ◽  
Specific Inhibitor ◽  
Amyloid Β ◽  
Neuronal Dysfunction ◽  
Channel Activation ◽  
Model Of Alzheimer’S Disease

AbstractBackgroundThe sequence of cellular dysfunctions in preclinical Alzheimer’s disease must be understood if we are to plot new therapeutic routes. Hippocampal neuronal hyperactivity is one of the earliest events occurring during the preclinical stages of Alzheimer’s disease in both humans and mouse models. The most common hypothesis describes amyloid β accumulation as the triggering factor of the disease but the effects of such accumulation and the cascade of events leading to cognitive decline remain unclear. In mice, we previously showed that amyloid β-dependent TRPA1 channel activation triggers hippocampal astrocyte hyperactivity, subsequently inducing hyperactivity in nearby neurons. In this work, we investigated the potential protection brought by an early chronic pharmacological inhibition of TRPA1 channel on Alzheimer’s disease progression.MethodsWe administered a specific inhibitor of TRPA1 channel (HC030031) intraperitoneally from the onset of amyloid β overproduction in the APP/PS1-21 mouse model of Alzheimer’s disease. We characterized short-, medium-, and long-term effects of this chronic pharmacological TRPA1 blockade on Alzheimer’s disease progression at functional (astrocytic and neuronal activity), structural, biochemical, and behavioural levels.ResultsOur results revealed that the first observable disruptions in the Alzheimer’s disease transgenic mouse model used correspond to aberrant hippocampal astrocyte and neuron hyperactivity. We showed that chronic TRPA1 blockade normalizes astrocytic activity, avoids perisynaptic astrocytic process withdrawal, prevents neuronal dysfunction, preserves structural synaptic integrity and strengthens the glial plaque barrier. These protective effects preserved spatial working-memory in this Alzheimer’s disease mouse model.ConclusionThe toxic effect of amyloid β on astrocytes triggered by TRPA1 channel activation is pivotal to Alzheimer’s disease progression. TRPA1 blockade prevent irreversible neuronal dysfunction, making this channel a potential therapeutic target to promote neuroprotection.

scholarly journals Cerebral hypoperfusion is a late pathological event in the course of Alzheimer's disease

2021 ◽  
Author(s):  
Khazar Ahmadi ◽  
Joana B. Pereira ◽  
David Berron ◽  
Jacob Vogel ◽  
Silvia Ingala ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Amyloid Β ◽  
Cognitive Status ◽  
Cerebral Hypoperfusion ◽  
Synaptic Dysfunction ◽  
Early Event ◽  
Preclinical Phase ◽  
Disease Progression Modeling

Although several studies have shown decreased cerebral blood flow (CBF) in Alzheimer's disease (AD), the role of hypoperfusion in the disease pathogenesis remains unclear. Combining arterial spin labeling MRI, positron emission tomography, and biomarkers of cerebrospinal fluid, we investigated the associations between CBF and the key mechanisms in AD including amyloid-β (Aβ) and tau pathology, synaptic dysfunction and axonal degeneration. Further, we applied a disease progression modeling to characterize the temporal sequence of different AD biomarkers. Lower perfusion was observed in the temporo-occipito-parietal regions in the Aβ-positive cognitively impaired compared to both the Aβ-positive and Aβ-negative cognitively unimpaired individuals. In participants along the AD spectrum (those with Aβ pathology regardless of their cognitive status), CBF was inversely associated with tau and synaptic dysfunction, but not Aβ in similar cortical regions. Moreover, the disease progression modeling revealed that CBF disruption followed the abnormality of biomarkers of Aβ, tau and brain atrophy. These findings indicate that tau tangles and synaptic degeneration are more closely connected with CBF changes rather than Aβ pathology. This supports the notion that hypoperfusion is not an early event associated with the build-up of Aβ during the preclinical phase of AD.

scholarly journals Application of Optogenetic Amyloid-β Distinguishes Between Metabolic and Physical Damage in Neurodegeneration

2019 ◽  
Author(s):  
Lim Chu Hsien ◽  
Prameet Kaur ◽  
Emelyne Teo ◽  
Vanessa Lam ◽  
Fangchen Zhu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Biological Effects ◽  
Amyloid Β ◽  
Tissue Loss ◽  
Amyloid Β Peptide ◽  
Physical Damage ◽  
Living Tissues

AbstractThe brains of Alzheimer’s Disease patients show a decrease in brain mass and a preponderance of extracellular Amyloid-β plaques. These plaques are formed by aggregation of polypeptides that are derived from Amyloid Precursor Protein (APP). Amyloid-β plaques are thought to play either a direct or an indirect role in disease progression, however the exact role of aggregation and plaque formation in the ethology of Alzheimer’s Disease is subject to debate, not least because the biological effects of soluble and aggregated Amyloid-β peptides are difficult to separate in vivo. To investigate the consequences of formation of Amyloid-β oligomers in living tissues, we developed a fluorescently tagged, optogenetic Amyloid-β peptide that oligomerizes rapidly in the presence of blue light. We applied this system to the crucial question of how intracellular Amyloid-β oligomers underlie the pathologies of Alzheimer’s Disease. We show that, although both expression and induced oligomerization of Amyloid-β were detrimental to lifespan and healthspan, we were able to separate the metabolic and physical damage caused by light-induced Amyloid-β oligomerization from Amyloid-β expression alone. The physical damage caused by Amyloid-β oligomers also recapitulated the catastrophic tissue loss that is a hallmark of late AD. We show that the lifespan deficit induced by Amyloid-β oligomers was reduced with Li+ treatment. Our results present the first model to separate different aspects of disease progression.

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