Cysteine protease inhibitors effectively reduce in vivo levels of brain β-amyloid related to Alzheimer's disease

AbstractAging increases the risk of Alzheimer’s disease (AD). During normal aging synapses decline and β-Amyloid (Aβ) accumulates. An Aβ defective clearance with aging is postulated as responsible for Aβ accumulation, although a role for increased Aβ production with aging can also lead to Aβ accumulation. To test this hypothesis, we established a long-term culture of primary mouse neurons that mimics neuronal aging (lysosomal lipofuscin accumulation and synapse decline). Intracellular endogenous Aβ42 accumulated in aged neurites due to increased amyloid-precursor protein (APP) processing. We show that APP processing is up-regulated by a specific age-dependent increase in APP endocytosis. Endocytosed APP accumulated in early endosomes that, in turn were found augmented in aged neurites. APP processing and early endosomes up-regulation was recapitulated in vivo. Finally, we found that inhibition of Aβ production reduced the decline in synapses in aged neurons. We propose that potentiation of APP endocytosis by neuronal aging increases Aβ production, which contributes to aging-dependent decline in synapses.SummaryHow aging increases the risk of Alzheimer’s disease is not clear. We show that normal neuronal aging increases the intracellular production of β-amyloid, due to an upregulation of the amyloid precursor protein endocytosis. Importantly, increased Aβ production contributes to the aging-dependent synapse loss.

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β-Amyloid Imaging In Vivo and Its Possible Implications for Alzheimer’s Disease

Nuclear Medicine in Psychiatry ◽

10.1007/978-3-642-18773-5_13 ◽

2004 ◽

pp. 191-199 ◽

Cited By ~ 1

Author(s):

N. P. L. G. Verhoeff ◽

A. A. Wilson ◽

H. F. Kung ◽

D. Hussey ◽

L. Trop ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Imaging ◽

Β Amyloid

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Prospective longitudinal atrophy in Alzheimer’s disease correlates with the intensity and topography of baseline tau-PET

Science Translational Medicine ◽

10.1126/scitranslmed.aau5732 ◽

2020 ◽

Vol 12 (524) ◽

pp. eaau5732 ◽

Cited By ~ 49

Author(s):

Renaud La Joie ◽

Adrienne V. Visani ◽

Suzanne L. Baker ◽

Jesse A. Brown ◽

Viktoriya Bourakova ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Pet ◽

Specific Distribution ◽

Positron Emission ◽

Pet Radiotracers ◽

Β Amyloid ◽

Tau Pet ◽

Prospective Longitudinal

β-Amyloid plaques and tau-containing neurofibrillary tangles are the two neuropathological hallmarks of Alzheimer’s disease (AD) and are thought to play crucial roles in a neurodegenerative cascade leading to dementia. Both lesions can now be visualized in vivo using positron emission tomography (PET) radiotracers, opening new opportunities to study disease mechanisms and improve patients’ diagnostic and prognostic evaluation. In a group of 32 patients at early symptomatic AD stages, we tested whether β-amyloid and tau-PET could predict subsequent brain atrophy measured using longitudinal magnetic resonance imaging acquired at the time of PET and 15 months later. Quantitative analyses showed that the global intensity of tau-PET, but not β-amyloid–PET, signal predicted the rate of subsequent atrophy, independent of baseline cortical thickness. Additional investigations demonstrated that the specific distribution of tau-PET signal was a strong indicator of the topography of future atrophy at the single patient level and that the relationship between baseline tau-PET and subsequent atrophy was particularly strong in younger patients. These data support disease models in which tau pathology is a major driver of local neurodegeneration and highlight the relevance of tau-PET as a precision medicine tool to help predict individual patient’s progression and design future clinical trials.

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Olive-Oil-Derived Oleocanthal Enhances β-Amyloid Clearance as a Potential Neuroprotective Mechanism against Alzheimer’s Disease: In Vitro and in Vivo Studies

ACS Chemical Neuroscience ◽

10.1021/cn400024q ◽

2013 ◽

Vol 4 (6) ◽

pp. 973-982 ◽

Cited By ~ 138

Author(s):

Alaa H. Abuznait ◽

Hisham Qosa ◽

Belnaser A. Busnena ◽

Khalid A. El Sayed ◽

Amal Kaddoumi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Olive Oil ◽

In Vivo Studies ◽

Β Amyloid

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Inhibition of Alzheimer's disease β‐amyloid aggregation, neurotoxicity, and in vivo deposition by nitrophenols: implications for Alzheimer's therapy

The FASEB Journal ◽

10.1096/fj.00-0676fje ◽

2001 ◽

Vol 15 (7) ◽

pp. 1297-1299 ◽

Cited By ~ 80

Author(s):

Fernanda G. Felice ◽

Jean-Christophe Houzel ◽

José Garcia-Abreu ◽

Paulo Roberto F. Louzada ◽

Rosenilde C. Afonso ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Aggregation ◽

Β Amyloid

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Methionine sulfoxide reductase A affects β-amyloid solubility and mitochondrial function in a mouse model of Alzheimer's disease

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00453.2015 ◽

2016 ◽

Vol 310 (6) ◽

pp. E388-E393 ◽

Cited By ~ 11

Author(s):

Jackob Moskovitz ◽

Fang Du ◽

Connor F. Bowman ◽

Shirley S. Yan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Methionine Sulfoxide ◽

Methionine Sulfoxide Reductase ◽

Methionine Sulfoxide Reductase A ◽

Model Of Alzheimer’S Disease ◽

Amyloid Aβ ◽

Β Amyloid

Accumulation of oxidized proteins, and especially β-amyloid (Aβ), is thought to be one of the common causes of Alzheimer's disease (AD). The current studies determine the effect of an in vivo methionine sulfoxidation of Aβ through ablation of the methionine sulfoxide reductase A (MsrA) in a mouse model of AD, a mouse that overexpresses amyloid precursor protein (APP) and Aβ in neurons. Lack of MsrA fosters the formation of methionine sulfoxide in proteins, and thus its ablation in the AD-mouse model will increase the formation of methionine sulfoxide in Aβ. Indeed, the novel MsrA-deficient APP mice ( APP+/ MsrAKO) exhibited higher levels of soluble Aβ in brain compared with APP+ mice. Furthermore, mitochondrial respiration and the activity of cytochrome c oxidase were compromised in the APP+/ MsrAKO compared with control mice. These results suggest that lower MsrA activity modifies Aβ solubility properties and causes mitochondrial dysfunction, and augmenting its activity may be beneficial in delaying AD progression.

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Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease in the Era of Disease-Modifying Treatments

Brain Sciences ◽

10.3390/brainsci11101258 ◽

2021 ◽

Vol 11 (10) ◽

pp. 1258

Author(s):

George P. Paraskevas ◽

Elisabeth Kapaki

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Small Vessel Disease ◽

Lewy Bodies ◽

Plaque Burden ◽

Csf Biomarkers ◽

Β Amyloid ◽

Disease Modifying

Correct in vivo diagnosis of Alzheimer’s disease (AD) helps to avoid administration of disease-modifying treatments in non-AD patients, and allows the possible use of such treatments in clinically atypical AD patients. Cerebrospinal fluid (CSF) biomarkers offer a tool for AD diagnosis. A reduction in CSF β-amyloid (marker of amyloid plaque burden), although compatible with Alzheimer’s pathological change, may also be observed in other dementing disorders, including vascular cognitive disorders due to subcortical small-vessel disease, dementia with Lewy bodies and normal-pressure hydrocephalus. Thus, for the diagnosis of AD, an abnormal result of CSF β-amyloid may not be sufficient, and an increase in phospho-tau (marker of tangle pathology) is also required in order to confirm AD diagnosis in patients with a typical amnestic presentation and reveal underlying AD in patients with atypical or mixed and diagnostically confusing clinical presentations.

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