scholarly journals Neurodegeneration and Astrogliosis in the Human ca1 Hippocampal Subfield Are Related to hsp90ab1 and bag3 in Alzheimer’s Disease

2021 ◽  
Vol 23 (1) ◽  
pp. 165
Author(s):  
Melania Gonzalez-Rodriguez ◽  
Sandra Villar-Conde ◽  
Veronica Astillero-Lopez ◽  
Patricia Villanueva-Anguita ◽  
Isabel Ubeda-Banon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Executive Dysfunction ◽  
Hippocampal Volume ◽  
P Value ◽  
Hippocampal Atrophy ◽  
Amyloid Β Peptide ◽  
Ms Analysis

Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder, is characterized by executive dysfunction and memory impairment mediated by the accumulation of extracellular amyloid-β peptide (Aβ) and intracellular hyperphosphorylated tau protein. The hippocampus (HIPP) is essential for memory formation and is involved in early stages of disease. In fact, hippocampal atrophy is used as an early biomarker of neuronal injury and to evaluate disease progression. It is not yet well-understood whether changes in hippocampal volume are due to neuronal or glial loss. The aim of the study was to assess hippocampal atrophy and/or gliosis using unbiased stereological quantification and to obtain hippocampal proteomic profiles related to neurodegeneration and gliosis. Hippocampal volume measurement, stereological quantification of NeuN-, Iba-1- and GFAP-positive cells, and sequential window acquisition of all theoretical mass spectrometry (SWATH-MS) analysis were performed in AD and non-AD cases. Reduced hippocampal volume was identified using the Cavalieri probe, particularly in the CA1 region, where it correlated with neuronal loss and astrogliosis. A total of 102 downregulated and 47 upregulated proteins were identified in the SWATH-MS analysis after restrictive filtering based on an FC >1.5 and p value < 0.01. The Hsp90 family of chaperones, particularly BAG3 and HSP90AB1, are closely related to astrocytes, indicating a possible role in degrading Aβ and tau through chaperone-mediated autophagy.

Impairment of the activity of the plasma membrane Ca2+-ATPase in Alzheimer's disease

2011 ◽  
Vol 39 (3) ◽  
pp. 819-822 ◽  
Author(s):  
Ana M. Mata ◽  
María Berrocal ◽  
M. Rosario Sepúlveda
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Inhibitory Effect ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid

AD (Alzheimer's disease) is an age-associated neurodegenerative disorder where the accumulation of neurotoxic Aβ (amyloid β-peptide) in senile plaques is a typical feature. Recent studies point out a relationship between Aβ neurotoxicity and Ca2+ dyshomoeostasis, but the molecular mechanisms involved are still under discussion. The PMCAs (plasma membrane Ca2+-ATPases) are a multi-isoform family of proteins highly expressed in brain that is implicated in the maintenance of low intraneural Ca2+ concentration. Therefore the malfunction of this pump may also be responsible for Ca2+ homoeostasis failure in AD. We have found that the Ca2+-dependence of PMCA activity is affected in human brains diagnosed with AD, being related to the enrichment of Aβ. The peptide produces an inhibitory effect on the activity of PMCA which is isoform-specific, with the greatest inhibition of PMCA4. Besides, cholesterol blocked the inhibitory effect of Aβ, which is consistent with the lack of any Aβ effect on PMCA4 found in cholesterol-enriched lipid rafts isolated from pig brain. These observations suggest that PMCAs are a functional component of the machinery that leads to Ca2+ dysregulation in AD and propose cholesterol enrichment in rafts as a protector of the Aβ-mediated inhibition on PMCA.

scholarly journals Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer’s disease mutations but not by inhibition of BACE1

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Erik C. B. Johnson ◽  
Kaitlyn Ho ◽  
Gui-Qiu Yu ◽  
Melanie Das ◽  
Pascal E. Sanchez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Neurodegenerative Disorder ◽  
Epileptiform Activity ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Aβ Oligomers ◽  
Behavioral Abnormalities ◽  
Amyloid Deposits

Abstract Background Alzheimer’s disease (AD) is the most frequent and costly neurodegenerative disorder. Although diverse lines of evidence suggest that the amyloid precursor protein (APP) is involved in its causation, the precise mechanisms remain unknown and no treatments are available to prevent or halt the disease. A favorite hypothesis has been that APP contributes to AD pathogenesis through the cerebral accumulation of the amyloid-β peptide (Aβ), which is derived from APP through sequential proteolytic cleavage by BACE1 and γ-secretase. However, inhibitors of these enzymes have failed in clinical trials despite clear evidence for target engagement. Methods To further elucidate the roles of APP and its metabolites in AD pathogenesis, we analyzed transgenic mice overexpressing wildtype human APP (hAPP) or hAPP carrying mutations that cause autosomal dominant familial AD (FAD), as well as App knock-in mice that do not overexpress hAPP but have two mouse App alleles with FAD mutations and a humanized Aβ sequence. Results Although these lines of mice had marked differences in cortical and hippocampal levels of APP, APP C-terminal fragments, soluble Aβ, Aβ oligomers and age-dependent amyloid deposition, they all developed cognitive deficits as well as non-convulsive epileptiform activity, a type of network dysfunction that also occurs in a substantive proportion of humans with AD. Pharmacological inhibition of BACE1 effectively reduced levels of amyloidogenic APP C-terminal fragments (C99), soluble Aβ, Aβ oligomers, and amyloid deposits in transgenic mice expressing FAD-mutant hAPP, but did not improve their network dysfunction and behavioral abnormalities, even when initiated at early stages before amyloid deposits were detectable. Conclusions hAPP transgenic and App knock-in mice develop similar pathophysiological alterations. APP and its metabolites contribute to AD-related functional alterations through complex combinatorial mechanisms that may be difficult to block with BACE inhibitors and, possibly, also with other anti-Aβ treatments.

Association between executive dysfunction and hippocampal volume in Alzheimer's disease

2010 ◽  
Vol 23 (5) ◽  
pp. 764-771 ◽  
Author(s):  
Tomoyuki Nagata ◽  
Shunichiro Shinagawa ◽  
Yusuke Ochiai ◽  
Ryo Aoki ◽  
Hiroo Kasahara ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Regional Analysis ◽  
Executive Dysfunction ◽  
Hippocampal Volume ◽  
Hippocampal Atrophy ◽  
Z Score ◽  
Clinical Dementia Rating ◽  
Early Alzheimer’S Disease

ABSTRACTBackground: Some previous research has hypothesized that executive dysfunction in patients with early Alzheimer's disease (AD) occurs as a result of a disconnection between different cerebral areas. The aim of the present study was to evaluate how the hippocampal volume influences executive function as a non-memory cognitive function.Methods: From 157 consecutive patients with AD or amnestic mild cognitive impairment (A-MCI), we recruited 107 subjects who had a global Clinical Dementia Rating (CDR) of 0.5 or 1.0 and whose degree of hippocampal atrophy had been measured using magnetic resonance imaging (MRI); the severity of atrophy was assessed using the voxel-based specific regional analysis for Alzheimer's disease (VSRAD) system. We divided the subjects into three groups: mild atrophy, 0 < Z-score < 1.0 (N = 21); moderate atrophy, 1.0 ≤ Z-score < 2.0 (N = 46); or severe atrophy, 2.0 ≤ Z-score < 4.0 (N = 40) according to the Z-score and compared the Frontal Assessment Battery (FAB) and its subtest scores between each atrophy group.Results: The results demonstrated that age, sex ratio, duration of illness, education years, MMSE score, Behave-AD score, and proportion of atrophy area in total brain (%) were not significantly different among the three groups. Only the go/no-go score among the six subtests was significantly lower for increasing atrophy severity (P < 0.05). Furthermore, hippocampal atrophy significantly influenced the go/no-go score independently of interactions from whether the diagnosis was early AD or A-MCI (P < 0.05).Conclusion: These results support a significant association between hippocampal atrophy and executive dysfunction as a non-memory cognitive impairment in patients with early AD and A-MCI.

scholarly journals Role of miRNAs in Alzheimer's Disease and Possible Fields of Application

2019 ◽  
Vol 20 (16) ◽  
pp. 3979 ◽  
Author(s):  
Silvestro ◽  
Bramanti ◽  
Mazzon
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Senile Dementia ◽  
Amyloid Β ◽  
Synaptic Function ◽  
In Vivo Studies ◽  
Transcriptional Gene Silencing ◽  
Amyloid Β Peptide

miRNAs (or microRNAs) are a class of single-stranded RNA molecules, responsible for post-transcriptional gene silencing through binding to the coding region as well as 3’ and 5’ untranslated region of target genes. About 70% of experimentally detectable miRNAs are expressed in the brain and some studies suggest that miRNAs are intimately involved in synaptic function and in specific signals during memory formation. More and more evidence demonstrates the possible involvement of miRNAs in Alzheimer's disease (AD). AD is the most common form of senile dementia, a disease that affects memory and cognitive functions. It is a neurodegenerative disorder characterized by loss of synapses, extracellular amyloid plaques composed of the amyloid-β peptide (Aβ), and intracellular aggregates of hyperphosphorylated TAU protein. This review aims to provide an overview of the in vivo studies of the last 5 years in the literature describing the role of the different miRNAs involved in AD. miRNAs hold huge potential as diagnostic and prognostic biomarkers and, at the same time, their modulation could be a potential therapeutic strategy against AD.

scholarly journals Effect of policosanol from insect wax on amyloid β-peptide-induced toxicity in a transgenic Caenorhabditis elegans model of Alzheimer’s disease

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xin Zhang ◽  
Chenjing Ma ◽  
Long Sun ◽  
Zhao He ◽  
Ying Feng ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Caenorhabditis Elegans ◽  
Life Span ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Health Concern ◽  
Amyloid Β Peptide ◽  
Model Of Alzheimer’S Disease ◽  
Age Related

Abstract Background Alzheimer’s disease (AD), an age-related neurodegenerative disorder and a serious public health concern, is mainly caused by β-amyloid (Aβ)-induced toxicity. Currently, a limited number of drugs are effective against AD, and only a few are used for its treatment. According to traditional Chinese medicine, white wax is mainly composed of policosanol, hexacosanol, and octacosanol. Policosanol has been shown to reduce lipid levels in blood and alleviate the symptoms associated with diabetic complications and neurodegenerative disorders, such as Parkinson’s disease and AD. However, the efficacy of policosanol depends on the purity and composition of the preparation, and the therapeutic efficacy of policosanol derived from insect wax (PIW) in AD is unknown. Methods Here, we identified the main components of PIW and investigated the effects of PIW on Aβ-induced toxicity and life-span in a transgenic Caenorhabditis elegans model of AD, CL4176. Furthermore, we estimated the expression of amyloid precursor-like protein (apl-1) and the genes involved in various pathways associated with longevity and alleviation of AD-related symptoms in PIW-fed CL4176. Results PIW mainly consists of tetracosanol, hexacosanol, octacosanol, and triacontanol; it could decrease the Aβ-induced paralysis rate from 86.87 to 66.97% (P < 0.01) and extend the life-span from 6.2 d to 7.8 d (P < 0.001) in CL4176 worms. Furthermore, PIW downregulated apl-1, a gene known to be associated with the levels of Aβ deposits in C. elegans. Additionally, our results showed that PIW modulated the expression of genes associated with longevity-related pathways such as heat shock response, anti-oxidative stress, and glutamine cysteine synthetase. Conclusion Our findings suggest that PIW may be a potential therapeutic agent for the prevention and treatment of AD. However, its effects on murine models and patients with AD need to be explored further.

scholarly journals The Conspicuous Link between Ear, Brain and Heart–Could Neurotrophin-Treatment of Age-Related Hearing Loss Help Prevent Alzheimer’s Disease and Associated Amyloid Cardiomyopathy?

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 900
Author(s):  
Sergey Shityakov ◽  
Kentaro Hayashi ◽  
Stefan Störk ◽  
Verena Scheper ◽  
Thomas Lenarz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
The Elderly ◽  
Amyloid Β Peptide ◽  
Age Related ◽  
Amyloid Cardiomyopathy ◽  
Age Related Hearing Loss

Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder associated with neurovascular dysfunction and cognitive decline. While the deposition of amyloid β peptide (Aβ) and the formation of neurofibrillary tangles (NFTs) are the pathological hallmarks of AD-affected brains, the majority of cases exhibits a combination of comorbidities that ultimately lead to multi-organ failure. Of particular interest, it can be demonstrated that Aβ pathology is present in the hearts of patients with AD, while the formation of NFT in the auditory system can be detected much earlier than the onset of symptoms. Progressive hearing impairment may beget social isolation and accelerate cognitive decline and increase the risk of developing dementia. The current review discusses the concept of a brain–ear–heart axis by which Aβ and NFT inhibition could be achieved through targeted supplementation of neurotrophic factors to the cochlea and the brain. Such amyloid inhibition might also indirectly affect amyloid accumulation in the heart, thus reducing the risk of developing AD-associated amyloid cardiomyopathy and cardiovascular disease.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Strong Support ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
Sequence Of Events ◽  
Aβ Amyloid ◽  
Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

Microglia in Alzheimer’s Disease

2020 ◽  
Vol 17 (1) ◽  
pp. 29-43 ◽  
Author(s):  
Patrick Süß ◽  
Johannes C.M. Schlachetzki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Imaging Techniques ◽  
Amyloid Β ◽  
Disease Stage ◽  
Disease Modifying Therapy ◽  
Transcriptomic Signature

: Alzheimer’s Disease (AD) is the most frequent neurodegenerative disorder. Although proteinaceous aggregates of extracellular Amyloid-β (Aβ) and intracellular hyperphosphorylated microtubule- associated tau have long been identified as characteristic neuropathological hallmarks of AD, a disease- modifying therapy against these targets has not been successful. An emerging concept is that microglia, the innate immune cells of the brain, are major players in AD pathogenesis. Microglia are longlived tissue-resident professional phagocytes that survey and rapidly respond to changes in their microenvironment. Subpopulations of microglia cluster around Aβ plaques and adopt a transcriptomic signature specifically linked to neurodegeneration. A plethora of molecules and pathways associated with microglia function and dysfunction has been identified as important players in mediating neurodegeneration. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage. : In this review, we summarize the current knowledge about the stage-dependent role of microglia in AD, including recent insights from genetic and gene expression profiling studies as well as novel imaging techniques focusing on microglia in human AD pathology and AD mouse models.

Is it All Said for NSAIDs in Alzheimer’s Disease? Role of Mitochondrial Calcium Uptake

2018 ◽  
Vol 15 (6) ◽  
pp. 504-510 ◽  
Author(s):  
Sara Sanz-Blasco ◽  
Maria Calvo-Rodríguez ◽  
Erica Caballero ◽  
Monica Garcia-Durillo ◽  
Lucia Nunez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Amyloid Β ◽  
Epidemiological Data ◽  
Amyloid Β Peptide ◽  
Aβ Oligomers ◽  
Mitochondrial Potential ◽  
Disease Modifying Drugs ◽  
Definitive Evidence

Objectives: Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Unfortunately, recent trials have failed in providing compelling evidence of neuroprotection. Discussion as to why NSAIDs effectivity is uncertain is ongoing. Possible explanations include the view that NSAIDs and other possible disease-modifying drugs should be provided before the patients develop symptoms of AD or cognitive decline. In addition, NSAID targets for neuroprotection are unclear. Both COX-dependent and independent mechanisms have been proposed, including γ-secretase that cleaves the amyloid precursor protein (APP) and yields amyloid β peptide (Aβ). Methods: We have proposed a neuroprotection mechanism for NSAIDs based on inhibition of mitochondrial Ca2+ overload. Aβ oligomers promote Ca2+ influx and mitochondrial Ca2+ overload leading to neuron cell death. Several non-specific NSAIDs including ibuprofen, sulindac, indomethacin and Rflurbiprofen depolarize mitochondria in the low µM range and prevent mitochondrial Ca2+ overload induced by Aβ oligomers and/or N-methyl-D-aspartate (NMDA). However, at larger concentrations, NSAIDs may collapse mitochondrial potential (ΔΨ) leading to cell death. Results: Accordingly, this mechanism may explain neuroprotection at low concentrations and damage at larger doses, thus providing clues on the failure of promising trials. Perhaps lower NSAID concentrations and/or alternative compounds with larger dynamic ranges should be considered for future trials to provide definitive evidence of neuroprotection against AD.

The Involvement of Post-Translational Modifications in Alzheimer's Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 313-335 ◽  
Author(s):  
Serena Marcelli ◽  
Massimo Corbo ◽  
Filomena Iannuzzi ◽  
Lucia Negri ◽  
Fabio Blandini ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Modification ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Normal Function ◽  
Ageing Population ◽  
Covalent Bonds ◽  
Post Translational Modifications ◽  
Related Proteins

Background: Alzheimer's disease (AD) is a neurodegenerative disorder recognized as the most common cause of chronic dementia among the ageing population. AD is histopathologically characterized by progressive loss of neurons and deposits of insoluble proteins, primarily composed of amyloid-β pelaques and neurofibrillary tangles (NFTs). Methods: Several molecular processes contribute to the formation of AD cellular hallmarks. Among them, post-translational modifications (PTMs) represent an attractive mechanism underlying the formation of covalent bonds between chemical groups/peptides to target proteins, which ultimately result modified in their function. Most of the proteins related to AD undergo PTMs. Several recent studies show that AD-related proteins like APP, Aβ, tau, BACE1 undergo post-translational modifications. The effect of PTMs contributes to the normal function of cells, although aberrant protein modification, which may depend on many factors, can drive the onset or support the development of AD. Results: Here we will discuss the effect of several PTMs on the functionality of AD-related proteins potentially contributing to the development of AD pathology. Conclusion: We will consider the role of Ubiquitination, Phosphorylation, SUMOylation, Acetylation and Nitrosylation on specific AD-related proteins and, more interestingly, the possible interactions that may occur between such different PTMs.

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