scholarly journals Amyloid-beta peptide and phosphorylated tau in the frontopolar cerebral cortex and in the cerebellum of toothed whales: aging versus hypoxia

Biology Open ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. bio054734
Author(s):  
Simona Sacchini ◽  
Josué Díaz-Delgado ◽  
Antonio Espinosa de los Monteros ◽  
Yania Paz ◽  
Yara Bernaldo de Quirós ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Neurofibrillary Tangle ◽  
Immunohistochemical Analysis ◽  
Granulovacuolar Degeneration ◽  
Beta Peptide ◽  
Cerebral Cortical Neurons ◽  
Beaked Whales ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Cerebellar Purkinje Neurons

ABSTRACTHypoxia could be a possible risk factor for neurodegenerative alterations in cetaceans’ brain. Among toothed whales, the beaked whales are particularly cryptic and routinely dive deeper than 1000 m for about 1 h in order to hunt squids and fishes. Samples of frontal cerebral and cerebellar cortex were collected from nine animals, representing six different species of the suborder Odontoceti. Immunohistochemical analysis employed anti-β-amyloid (Aβ) and anti-neurofibrillary tangle (NFT) antibodies. Six of nine (67%) animals showed positive immunolabeling for Aβ and/or NFT. The most striking findings were intranuclear Aβ immunopositivity in cerebral cortical neurons and NFT immunopositivity in cerebellar Purkinje neurons with granulovacuolar degeneration. Aβ plaques were also observed in one elderly animal. Herein, we present immunohistopathological findings classic of Alzheimer's and other neurodegenerative diseases in humans. Our findings could be linked to hypoxic phenomena, as they were more extensive in beaked whales. Despite their adaptations, cetaceans could be vulnerable to sustained and repetitive brain hypoxia.

scholarly journals Amyloid-beta peptide and phosphorylated tau in the frontopolar cerebral cortex and in the cerebellum of toothed whales: aging vs hypoxia

2020 ◽  
Author(s):  
Simona Sacchini ◽  
Josué Díaz ◽  
Antonio Espinosa de los Monteros ◽  
Yania Paz ◽  
Yara Bernaldo de Quirós ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebral Cortex ◽  
Neurodegenerative Diseases ◽  
Cortical Neurons ◽  
Neurofibrillary Tangle ◽  
Immunohistochemical Analysis ◽  
Granulovacuolar Degeneration ◽  
Beaked Whales ◽  
The Brain

Abstract Background: Alzheimer’s disease results from the interplay of multiple risk factors and their effects. Diving mammals may be routinely exposed to severe hypoxia when submerged. Among toothed whales, the beaked whales are particularly cryptic and routinely dive deeper than 1,000 m for about one hour in order to hunt deep-water squid and fish. We hypothesized that hypoxia could be a possible risk factor for neurodegenerative alterations in the central nervous system of beaked whales in particular, and toothed whales in general. Results: Samples of frontal cerebral cortex and cerebellum were collected from nine animals, representing six different species of the suborder Odontoceti. Immunohistochemical analysis employed a monoclonal anti-β-amyloid (Aβ) and a polyclonal anti-neurofibrillary tangle (NFT) antibodies. Six of nine (67%) animals showed positive immunolabeling for Aβ and/or NFT. The most striking findings were intranuclear Aβ immunopositivity in cerebral cortical neurons and NFT immunopositivity in cerebellar Purkinje neurons with granulovacuolar degeneration. Herein, we present immunohistopathological findings classic of Alzheimer’s and other neurodegenerative diseases in humans, in different brain locales of odontocete cetaceans. This study represents the first description of Aβ and NFT in the brain of beaked whales, adding also to the non-existent descriptions of GVD in the brain of non-experimental animals, being specifically the first report of granulovacuolar degeneration in the cerebellum. Our results further confirm the rarely reported intranuclear expression of Aβ. Conclusions: These findings could be linked to hypoxic phenomena, as they were more extensive in the brains of beaked whales, and not only in aged individuals. Therefore, a novel hypothesis linking hypoxia and neurodegeneration microscopic hallmarks in cetaceans is proposed. Despite their adaptations, diving mammals could be vulnerable to sustained and repetitive brain hypoxia. Future comparative pathological and neuroprotective investigations may prove of great value to Alzheimer’s disease and other neurodegenerative diseases in humans.

scholarly journals Oxidative Stress and Beta Amyloid in Alzheimer’s Disease. Which Comes First: The Chicken or the Egg?

Antioxidants ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1479
Author(s):  
Elena Tamagno ◽  
Michela Guglielmotto ◽  
Valeria Vasciaveo ◽  
Massimo Tabaton
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangle ◽  
Metabolic Dysfunction ◽  
Antioxidant Treatment ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Ad Alzheimer’S Disease ◽  
Important Therapeutic Target

The pathogenesis of Alzheimer’s disease involves β amyloid (Aβ) accumulation known to induce synaptic dysfunction and neurodegeneration. The brain’s vulnerability to oxidative stress (OS) is considered a crucial detrimental factor in Alzheimer’s disease. OS and Aβ are linked to each other because Aβ induces OS, and OS increases the Aβ deposition. Thus, the answer to the question “which comes first: the chicken or the egg?” remains extremely difficult. In any case, the evidence for the primary occurrence of oxidative stress in AD is attractive. Thus, evidence indicates that a long period of gradual oxidative damage accumulation precedes and results in the appearance of clinical and pathological AD symptoms, including Aβ deposition, neurofibrillary tangle formation, metabolic dysfunction, and cognitive decline. Moreover, oxidative stress plays a crucial role in the pathogenesis of many risk factors for AD. Alzheimer’s disease begins many years before its symptoms, and antioxidant treatment can be an important therapeutic target for attacking the disease.

Trophic effect of β-amyloid precursor protein on cerebral cortical neurons in culture

1991 ◽  
Vol 181 (1) ◽  
pp. 265-271 ◽  
Author(s):  
Wataru Araki ◽  
Nobuya Kitaguchi ◽  
Yasuo Tokushima ◽  
Kazuhiro Ishii ◽  
Hisashi Aratake ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Cortical Neurons ◽  
Precursor Protein ◽  
Trophic Effect ◽  
Cerebral Cortical Neurons ◽  
Β Amyloid

Amentoflavone: A Bifunctional Metal Chelator that Controls the Formation of Neurotoxic Soluble Aβ42 Oligomers

2020 ◽  
Author(s):  
Liang Sun ◽  
Anuj K. Sharma ◽  
Byung-Hee Han ◽  
Liviu M. Mirica
Keyword(s):  
Reactive Oxygen Species ◽  
Metal Ions ◽  
Antioxidant Properties ◽  
Reactive Oxygen ◽  
Amyloid Plaques ◽  
Transition Metal Ions ◽  
Oxygen Species ◽  
High Affinity ◽  
Amyloid Aβ ◽  
Β Amyloid

<p>Alzheimer's disease (AD) is the most common neurodegenerative disorder, yet the cause and progression of this disorder are not completely understood. While the main hallmark of AD is the deposition of amyloid plaques consisting of the β-amyloid (Aβ) peptide, transition metal ions are also known to play a significant role in disease pathology by expediting the formation of neurotoxic soluble β-amyloid (Aβ) oligomers, reactive oxygen species (ROS), and oxidative stress. Thus, bifunctional metal chelators that can control these deleterious properties are highly desirable. Herein, we show that amentoflavone (AMF) – a natural biflavonoid compound, exhibits good metal-chelating properties, especially for chelating Cu<sup>2+</sup> with very high affinity (pCu<sub>7.4</sub> = 10.44). In addition, AMF binds to Aβ fibrils with a high affinity (<i>K<sub>i</sub></i> = 287 ± 20 nM) – as revealed by a competition thioflavin T (ThT) assay, and specifically labels the amyloid plaques <i>ex vivo</i> in the brain sections of transgenic AD mice – as confirmed via immunostaining with an Ab antibody. The effect of AMF on Aβ<sub>42</sub> aggregation and disaggregation of Aβ<sub>42</sub> fibrils was also investigated, to reveal that AMF can control the formation of neurotoxic soluble Aβ<sub>42</sub> oligomers, both in absence and presence of metal ions, and as confirmed via cell toxicity studies. Furthermore, an ascorbate consumption assay shows that AMF exhibits potent antioxidant properties and can chelate Cu<sup>2+</sup> and significantly diminish the Cu<sup>2+</sup>-ascorbate redox cycling and reactive oxygen species (ROS) formation. Overall, these studies strongly suggest that AMF acts as a bifunctional chelator that can interact with various Aβ aggregates and reduce their neurotoxicity, can also bind Cu<sup>2+</sup> and mediate its deleterious redox properties, and thus AMF has the potential to be a lead compound for further therapeutic agent development for AD. </p>

MiR-335-5p Inhibits β-Amyloid (Aβ) Accumulation to Attenuate Cognitive Deficits Through Targeting c-jun-N-terminal Kinase 3 in Alzheimer’s Disease

2020 ◽  
Vol 17 (1) ◽  
pp. 93-101 ◽  
Author(s):  
Dan Wang ◽  
Zhifu Fei ◽  
Song Luo ◽  
Hai Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Western Blot ◽  
Mrna Expression ◽  
Cognitive Deficits ◽  
Protein Levels ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
The Relationship

Objectives: Alzheimer's disease (AD), also known as senile dementia, is a common neurodegenerative disease characterized by progressive cognitive impairment and personality changes. Numerous evidences have suggested that microRNAs (miRNAs) are involved in the pathogenesis and development of AD. However, the exact role of miR-335-5p in the progression of AD is still not clearly clarified. Methods: The protein and mRNA levels were measured by western blot and RNA extraction and quantitative real-time PCR (qRT-PCR), respectively. The relationship between miR-335-5p and c-jun-N-terminal kinase 3 (JNK3) was confirmed by dual-luciferase reporter assay. SH-SY5Y cells were transfected with APP mutant gene to establish the in vitro AD cell model. Flow cytometry and western blot were performed to evaluate cell apoptosis. The APP/PS1 transgenic mice were used as an in vivo AD model. Morris water maze test was performed to assess the effect of miR- 335-5p on the cognitive deficits in APP/PS1 transgenic mice. Results: The JNK3 mRNA expression and protein levels of JNK3 and β-Amyloid (Aβ) were significantly up-regulated, and the mRNA expression of miR-335-5p was down-regulated in the brain tissues of AD patients. The expression levels of miR-335-5p and JNK3 were significantly inversely correlated. Further, the dual Luciferase assay verified the relationship between miR-335- 5p and JNK3. Overexpression of miR-335-5p significantly decreased the protein levels of JNK3 and Aβ and inhibited apoptosis in SH-SY5Y/APPswe cells, whereas the inhibition of miR-335-5p obtained the opposite results. Moreover, the overexpression of miR-335-5p remarkably improved the cognitive abilities of APP/PS1 mice. Conclusion: The results revealed that the increased JNK3 expression, negatively regulated by miR-335-5p, may be a potential mechanism that contributes to Aβ accumulation and AD progression, indicating a novel approach for AD treatment.

The Protective Effects of Jatrorrhizine on β-Amyloid (25-35)-Induced Neurotoxicity in Rat Cortical Neurons

2013 ◽  
Vol 11 (8) ◽  
pp. 1030-1037 ◽  
Author(s):  
Tao Luo ◽  
Wei Jiang ◽  
Yan Kong ◽  
Sheng Li ◽  
Feng He ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Protective Effects ◽  
Rat Cortical Neurons ◽  
Β Amyloid

scholarly journals Long-Term Caloric Restriction Attenuates β-Amyloid Neuropathology and Is Accompanied by Autophagy in APPswe/PS1delta9 Mice

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 985
Author(s):  
Luisa Müller ◽  
Nicole Power Guerra ◽  
Jan Stenzel ◽  
Claire Rühlmann ◽  
Tobias Lindner ◽  
...  
Keyword(s):  
Caloric Restriction ◽  
Neuroprotective Effect ◽  
Resonance Spectroscopy ◽  
Neuroprotective Effects ◽  
Beneficial Effects ◽  
Positron Emission ◽  
Pet Ct ◽  
Amyloid Aβ ◽  
Β Amyloid

Caloric restriction (CR) slows the aging process, extends lifespan, and exerts neuroprotective effects. It is widely accepted that CR attenuates β-amyloid (Aβ) neuropathology in models of Alzheimer’s disease (AD) by so-far unknown mechanisms. One promising process induced by CR is autophagy, which is known to degrade aggregated proteins such as amyloids. In addition, autophagy positively regulates glucose uptake and may improve cerebral hypometabolism—a hallmark of AD—and, consequently, neural activity. To evaluate this hypothesis, APPswe/PS1delta9 (tg) mice and their littermates (wild-type, wt) underwent CR for either 16 or 68 weeks. Whereas short-term CR for 16 weeks revealed no noteworthy changes of AD phenotype in tg mice, long-term CR for 68 weeks showed beneficial effects. Thus, cerebral glucose metabolism and neuronal integrity were markedly increased upon 68 weeks CR in tg mice, indicated by an elevated hippocampal fluorodeoxyglucose [18F] ([18F]FDG) uptake and increased N-acetylaspartate-to-creatine ratio using positron emission tomography/computer tomography (PET/CT) imaging and magnet resonance spectroscopy (MRS). Improved neuronal activity and integrity resulted in a better cognitive performance within the Morris Water Maze. Moreover, CR for 68 weeks caused a significant increase of LC3BII and p62 protein expression, showing enhanced autophagy. Additionally, a significant decrease of Aβ plaques in tg mice in the hippocampus was observed, accompanied by reduced microgliosis as indicated by significantly decreased numbers of iba1-positive cells. In summary, long-term CR revealed an overall neuroprotective effect in tg mice. Further, this study shows, for the first time, that CR-induced autophagy in tg mice accompanies the observed attenuation of Aβ pathology.

scholarly journals Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology

2021 ◽  
Vol 7 (21) ◽  
pp. eabe4601
Author(s):  
Sandro Da Mesquita ◽  
Jasmin Herz ◽  
Morgan Wall ◽  
Taitea Dykstra ◽  
Kalil Alves de Lima ◽  
...  
Keyword(s):  
T Cells ◽  
Cognitive Decline ◽  
Brain Aging ◽  
Therapeutic Potential ◽  
T Cell Response ◽  
Age Related ◽  
Lymphatic Vasculature ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Old Mice

Aging leads to a progressive deterioration of meningeal lymphatics and peripheral immunity, which may accelerate cognitive decline. We hypothesized that an age-related reduction in C-C chemokine receptor type 7 (CCR7)–dependent egress of immune cells through the lymphatic vasculature mediates some aspects of brain aging and potentially exacerbates cognitive decline and Alzheimer’s disease–like brain β-amyloid (Aβ) pathology. We report a reduction in CCR7 expression by meningeal T cells in old mice that is linked to increased effector and regulatory T cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to reduced glymphatic influx and cognitive impairment. Deletion of CCR7 in 5xFAD transgenic mice resulted in deleterious neurovascular and microglial activation, along with increased Aβ deposition in the brain. Treating old mice with anti-CD25 antibodies alleviated the exacerbated meningeal regulatory T cell response and improved cognitive function, highlighting the therapeutic potential of modulating meningeal immunity to fine-tune brain function in aging and in neurodegenerative diseases.

Evidence that iron accelerates Alzheimer’s pathology: a CSF biomarker study

2017 ◽  
Vol 89 (5) ◽  
pp. 456-460 ◽  
Author(s):  
Scott Ayton ◽  
Ibrahima Diouf ◽  
Ashley Ian Bush
Keyword(s):  
Disease Process ◽  
Threshold Value ◽  
Simulation Modelling ◽  
Longitudinal Changes ◽  
Accelerated Depreciation ◽  
History Of ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Using Data ◽  
Alzheimer’S Pathology

ObjectiveTo investigate whether cerebrospinal fluid (CSF) ferritin (reporting brain iron) is associated with longitudinal changes in CSF β-amyloid (Aβ) and tau.MethodsMixed-effects models of CSF Aβ1-42 and tau were constructed using data from 296 participants who had baseline measurement of CSF ferritin and annual measurement of CSF tau and Aβ1-42 for up to 5 years.ResultsIn subjects with biomarker-confirmed Alzheimer’s pathology, high CSF ferritin (>6.2 ng/mL) was associated with accelerated depreciation of CSF Aβ1-42 (reporting increased plaque formation; p=0.0001). CSF ferritin was neither associated with changes in CSF tau in the same subjects, nor longitudinal changes in CSF tau or Aβ1-42 in subjects with low baseline pathology. In simulation modelling of the natural history of Aβ deposition, which we estimated to occur over 31.4 years, we predicted that it would take 12.6 years to reach the pathology threshold value of CSF Aβ from healthy normal levels, and this interval is not affected by CSF ferritin. CSF ferritin influences the fall in CSF Aβ over the next phase, where high CSF ferritin accelerated the transition from threshold preclinical Aβ levels to the average level of Alzheimer’s subjects from 18.8 to 10.8 years.ConclusionsIron might facilitate Aβ deposition in Alzheimer’s and accelerate the disease process.

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