scholarly journals Amyloid-Driven Tau Accumulation on Mitochondria Potentially Leads to Cognitive Deterioration in Alzheimer’s Disease

2021 ◽  
Vol 22 (21) ◽  
pp. 11950
Author(s):  
Mar Cuadrado-Tejedor ◽  
Marta Pérez-González ◽  
Rocío Alfaro-Ruiz ◽  
Sara Badesso ◽  
Diego Sucunza ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Memory Function ◽  
Immunohistochemical Analysis ◽  
Adeno Associated Virus ◽  
Biochemical Assays ◽  
Β Amyloid ◽  
Tau Aggregation ◽  
Specific Contribution

Despite the well-accepted role of the two main neuropathological markers (β-amyloid and tau) in the progression of Alzheimer’s disease, the interaction and specific contribution of each of them is not fully elucidated. To address this question, in the present study, an adeno-associated virus (AAV9) carrying the mutant P301L form of human tau, was injected into the dorsal hippocampi of APP/PS1 transgenic mice or wild type mice (WT). Three months after injections, memory tasks, biochemical and immunohistochemical analysis were performed. We found that the overexpression of hTauP301L accelerates memory deficits in APP/PS1 mice, but it did not affect memory function of WT mice. Likewise, biochemical assays showed that only in the case of APP/PS1-hTauP301L injected mice, an important accumulation of tau was observed in the insoluble urea fraction. Similarly, electron microscopy images revealed that numerous clusters of tau immunoparticles appear at the dendrites of APP/PS1 injected mice and not in WT animals, suggesting that the presence of amyloid is necessary to induce tau aggregation. Interestingly, these tau immunoparticles accumulate in dendritic mitochondria in the APP/PS1 mice, whereas most of mitochondria in WT injected mice remain free of tau immunoparticles. Taken together, it seems that amyloid induces tau aggregation and accumulation in the dendritic mitochondria and subsequently may alter synapse function, thus, contributing to accelerate cognitive decline in APP/PS1 mice.

Alzheimer’s disease pathogenesis is dependent on neuronal receptor PTPσ

2016 ◽  
Author(s):  
Yuanzheng Gu ◽  
Yaoling Shu ◽  
Angela W. Corona ◽  
Kui Xu ◽  
Allen F. Yi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Behavioral Deficits ◽  
Amyloid Accumulation ◽  
Β Amyloid ◽  
Neuronal Receptor ◽  
Tau Aggregation

β-amyloid accumulation and Tau aggregation are hallmarks of Alzheimer’s disease, yet their underlying molecular mechanisms remain obscure, hindering therapeutic advances. Here we report that neuronal receptor PTPσ mediates both β-amyloid and Tau pathogenesis in two mouse models. In the brain, PTPσ binds to β-amyloid precursor protein (APP). Depletion of PTPσ reduces the affinity between APP and β-secretase, diminishing APP proteolytic products by β- and γ-cleavage without affecting other major substrates of the secretases, suggesting a specificity of β-amyloidogenic regulation. In human APP transgenic mice during aging, the progression of β-amyloidosis, Tau aggregation, neuroinflammation, synaptic loss, as well as behavioral deficits, all show unambiguous dependency on the expression of PTPσ. Additionally, the aggregates of endogenous Tau are found in a distribution pattern similar to that of early stage neurofibrillary tangles in Alzheimer brains. Together, these findings unveil a gatekeeping role of PTPσ upstream of the degenerative pathogenesis, indicating a potential for this neuronal receptor as a drug target for Alzheimer’s disease.

scholarly journals Microglia in Alzheimer’s Disease: A Target for Therapeutic Intervention

2021 ◽  
Vol 15 ◽  
Author(s):  
Guimei Zhang ◽  
Zicheng Wang ◽  
Huiling Hu ◽  
Meng Zhao ◽  
Li Sun
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Interventions ◽  
Tau Pathology ◽  
Age Related ◽  
Amyloid Accumulation ◽  
Pathophysiological Role ◽  
Inflammatory Drugs ◽  
Β Amyloid

Alzheimer’s disease (AD) is one of the most common types of age-related dementia worldwide. In addition to extracellular amyloid plaques and intracellular neurofibrillary tangles, dysregulated microglia also play deleterious roles in the AD pathogenesis. Numerous studies have demonstrated that unbridled microglial activity induces a chronic neuroinflammatory environment, promotes β-amyloid accumulation and tau pathology, and impairs microglia-associated mitophagy. Thus, targeting microglia may pave the way for new therapeutic interventions. This review provides a thorough overview of the pathophysiological role of the microglia in AD and illustrates the potential avenues for microglia-targeted therapies, including microglial modification, immunoreceptors, and anti-inflammatory drugs.

scholarly journals ROLE OF PATHOGENIC PROTEINS AND CHRONIC INFLAMMATION IN THE OCCURRENCE OF ALZHEIMER'S DISEASE

2020 ◽  
Vol 8 (4) ◽  
pp. 475-490
Author(s):  
A.P. Denysenko ◽  
O.O. Haikova ◽  
R.A. Moskalenko
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Economic Significance ◽  
Leading Role ◽  
Vascular Insufficiency ◽  
Scientific Papers ◽  
Long Time ◽  
Β Amyloid ◽  
Key Terms

Alzheimer's disease is the most common form of dementia affecting up to 70% of all patients with dementia. Currently, the relevance of this neurodegenerative disease has increased due to its prevalence and lack of etiological and effective treatment. The consequence of this is an increase in the number of studies and scientific works aimed at studying this disease. The aim of the study was to analyze and systematize data on the prevalence, socioeconomic significance, theories of origin, as well as the role of pathogenic proteins in the development of Alzheimer's disease. The authors searched for information in electronic databases such as PubMed and Google Scholar, with scientific papers and articles from the last 25 years on such key terms as Alzheimer's disease, β-amyloid, tau-peptide, metals, inflammation, S100 proteins. There are more than 56 million people with Alzheimer's disease in the world and the risk increases with age. Among the causes of death, Alzheimer's disease ranks sixth, and the costs of care about person with this diagnosis are three times higher than for other diseases in the same age group. That is why this issue has significant socio-economic significance. Many hypotheses have emerged in recent decades. For a long time, the theory of β-amyloid aggregation and the theory of tau protein were considered main, but later the priorities began to change. It has been found that the presence of pathogenic microorganisms can pose a risk for Alzheimer's disease. Also, some studies indicate the role of acetylcholine in the development of the disease, however, clinical trials have not confirmed this. There is a violation of metal homeostasis, which contributes to cognitive deficits and the development of neurodegeneration. Microglia, astrocytes and neurons are involved in the inflammatory process in Alzheimer's disease. There is a vicious circle when Aβ causes vascular insufficiency, which in turn leads to an increase in Aβ accumulation. Also there is evidence of a direct relationship between oxidative stress and neuronal dysfunction. Undoubtedly, pathogenic proteins, including Aβ-peptide, tau-peptide and proteins of the S100 family, play a leading role in the development of Alzheimer's disease. Despite numerous studies, the causal or consequential role of various pathological factors and changes in Alzheimer's disease is still ambiguous and inconsistent. All this gives grounds for further scientific research in this direction.

scholarly journals Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer’s disease mice

2022 ◽  
Vol 119 (3) ◽  
pp. e2115082119
Author(s):  
Min Hee Park ◽  
Kang Ho Park ◽  
Byung Jo Choi ◽  
Wan Hui Han ◽  
Hee Ji Yoon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Memory Function ◽  
Selective Inhibition ◽  
Acid Sphingomyelinase ◽  
Hippocampal Neurogenesis ◽  
Ghrelin Receptor ◽  
Dual Action

Alzheimer’s disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.

scholarly journals A lipid-invasion model for Alzheimer’s Disease

2019 ◽  
Author(s):  
Jonathan D Rudge
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Principal Role ◽  
Lipid Droplet Formation ◽  
Invasion Model ◽  
Β Amyloid ◽  
Mass Influx ◽  
The Brain

This paper describes a potential new explanation for Alzheimer’s disease (AD), referred to here as the lipid-invasion model. It proposes that AD is primarily caused by the influx of lipids following the breakdown of the blood brain barrier (BBB). The model argues that a principal role of the BBB is to protect the brain from external lipid access. When the BBB is damaged, it allows a mass influx of (mainly albumin-bound) free fatty acids (FFAs) and lipid-rich lipoproteins to the brain, which in turn causes neurodegeneration, amyloidosis, tau tangles and other AD characteristics. The model also argues that, whilst β-amyloid causes neurodegeneration, as is widely argued, its principal role in the disease lies in damaging the BBB. It is the external lipids, entering as a consequence, that are the primary drivers of neurodegeneration in AD., especially FFAs, which induce oxidative stress, stimulate microglia-driven neuroinflammation, and inhibit neurogenesis. Simultaneously, the larger, more lipid-laden lipoproteins, characteristic of the external plasma but not the CNS, cause endosomal-lysosomal abnormalities, amyloidosis and the formation of tau tangles, all characteristic of AD. In most cases (certainly in late-onset, noninherited forms of the disease) amyloidosis and tau tangle formation are consequences of this external lipid invasion, and in many ways more symptomatic of the disease than causative. In support of this, it is argued that the pattern of damage caused by the influx of FFAs into the brain is likely to resemble the neurodegeneration seen in alcohol-related brain damage (ARBD), a disease that shows many similarities to AD, including the areas of the brain it affects. The fact that neurodegeneration is far more pronounced in AD than in ARBD, and characterised by other features, such as amyloidosis and tau tangles, most likely results from the greater heterogeneity of the lipid assault in AD compared with ethanol alone. The lipid-invasion model, described here, arguably provides the first cohesive, multi-factorial explanation of AD that accounts for all currently known major risk factors, and explains all AD-associated pathologies, including those, such as endosomal-lysosomal dysfunction and excessive lipid droplet formation, that are not well-accounted for in other explanation of this disease.

scholarly journals A lipid-invasion model for Alzheimer’s Disease

2019 ◽  
Author(s):  
Jonathan D Rudge
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Late Onset ◽  
Principal Role ◽  
Lipid Droplet Formation ◽  
Invasion Model ◽  
Β Amyloid ◽  
Mass Influx ◽  
The Brain

This paper describes a potential new explanation for Alzheimer’s disease (AD), referred to here as the lipid-invasion model. It proposes that AD is primarily caused by the influx of lipids following the breakdown of the blood brain barrier (BBB). The model argues that a principal role of the BBB is to protect the brain from external lipid access. When the BBB is damaged, it allows a mass influx of (mainly albumin-bound) free fatty acids (FFAs) and lipid-rich lipoproteins to the brain, which in turn causes neurodegeneration, amyloidosis, tau tangles and other AD characteristics. The model also argues that, whilst β-amyloid causes neurodegeneration, as is widely argued, its principal role in the disease lies in damaging the BBB. It is the external lipids, entering as a consequence, that are the primary drivers of neurodegeneration in AD., especially FFAs, which induce oxidative stress, stimulate microglia-driven neuroinflammation, and inhibit neurogenesis. Simultaneously, the larger, more lipid-laden lipoproteins, characteristic of the external plasma but not the CNS, cause endosomal-lysosomal abnormalities, amyloidosis and the formation of tau tangles, all characteristic of AD. In most cases (certainly in late-onset, noninherited forms of the disease) amyloidosis and tau tangle formation are consequences of this external lipid invasion, and in many ways more symptomatic of the disease than causative. In support of this, it is argued that the pattern of damage caused by the influx of FFAs into the brain is likely to resemble the neurodegeneration seen in alcohol-related brain damage (ARBD), a disease that shows many similarities to AD, including the areas of the brain it affects. The fact that neurodegeneration is far more pronounced in AD than in ARBD, and characterised by other features, such as amyloidosis and tau tangles, most likely results from the greater heterogeneity of the lipid assault in AD compared with ethanol alone. The lipid-invasion model, described here, arguably provides the first cohesive, multi-factorial explanation of AD that accounts for all currently known major risk factors, and explains all AD-associated pathologies, including those, such as endosomal-lysosomal dysfunction and excessive lipid droplet formation, that are not well-accounted for in other explanation of this disease.

scholarly journals Functional Foods: An Approach to Modulate Molecular Mechanisms of Alzheimer’s Disease

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2347
Author(s):  
Anna Atlante ◽  
Giuseppina Amadoro ◽  
Antonella Bobba ◽  
Valentina Latina
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Food Product ◽  
Neuroprotective Effects ◽  
The Road ◽  
Beneficial Effects ◽  
Β Amyloid ◽  
The Brain

A new epoch is emerging with intense research on nutraceuticals, i.e., “food or food product that provides medical or health benefits including the prevention and treatment of diseases”, such as Alzheimer’s disease. Nutraceuticals act at different biochemical and metabolic levels and much evidence shows their neuroprotective effects; in particular, they are able to provide protection against mitochondrial damage, oxidative stress, toxicity of β-amyloid and Tau and cell death. They have been shown to influence the composition of the intestinal microbiota significantly contributing to the discovery that differential microorganisms composition is associated with the formation and aggregation of cerebral toxic proteins. Further, the routes of interaction between epigenetic mechanisms and the microbiota–gut–brain axis have been elucidated, thus establishing a modulatory role of diet-induced epigenetic changes of gut microbiota in shaping the brain. This review examines recent scientific literature addressing the beneficial effects of some natural products for which mechanistic evidence to prevent or slowdown AD are available. Even if the road is still long, the results are already exceptional.

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