scholarly journals Amyloid β 1-42 deposits do not lead to Alzheimer's neuritic plaques in aged dogs

1996 ◽  
Vol 313 (2) ◽  
pp. 575-580 ◽  
Author(s):  
Thomas WISNIEWSKI ◽  
Maciej LALOWSKI ◽  
Marketta BOBIK ◽  
Michael RUSSELL ◽  
Joanna STROSZNAJDER ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Plaque Formation ◽  
Neuritic Plaque ◽  
Amyloid Angiopathy ◽  
Neuritic Plaques ◽  
Cerebral Vessel ◽  
Aβ Peptides

In Alzheimer's disease, amyloid β (Aβ) is deposited in senile plaques and amyloid angiopathy. Longer Aβ peptides, which extend to residue 42 (Aβ42), have been suggested to be critical for the seeding of amyloid. Aged dogs develop cerebral vessel amyloid and parenchymal preamyloid lesions. Preamyloid in humans is related to senile plaques, whereas in dogs such progression is rare. We evaluated the composition of aged canine vessel amyloid and preamyloid both biochemically and immunohistochemically. The vessel amyloid extended mainly to residue 40 (Aβ40), while preamyloid contained a mixture of Aβ17-42 and Aβ42, with minimal Aβ40. Our results suggest other factors besides Aβ42 are important for neuritic plaque formation.

scholarly journals Valproic acid inhibits Aβ production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models

2008 ◽  
Vol 205 (12) ◽  
pp. 2781-2789 ◽  
Author(s):  
Hong Qing ◽  
Guiqiong He ◽  
Philip T. T. Ly ◽  
Christopher J. Fox ◽  
Matthias Staufenbiel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Valproic Acid ◽  
Amyloid Β ◽  
Memory Deficits ◽  
Plaque Formation ◽  
Neuritic Plaque ◽  
Amyloid Β Protein ◽  
Neuritic Plaques ◽  
Aβ Production

Neuritic plaques in the brains are one of the pathological hallmarks of Alzheimer's disease (AD). Amyloid β-protein (Aβ), the central component of neuritic plaques, is derived from β-amyloid precursor protein (APP) after β- and γ-secretase cleavage. The molecular mechanism underlying the pathogenesis of AD is not yet well defined, and there has been no effective treatment for AD. Valproic acid (VPA) is one of the most widely used anticonvulsant and mood-stabilizing agents for treating epilepsy and bipolar disorder. We found that VPA decreased Aβ production by inhibiting GSK-3β–mediated γ-secretase cleavage of APP both in vitro and in vivo. VPA treatment significantly reduced neuritic plaque formation and improved memory deficits in transgenic AD model mice. We also found that early application of VPA was important for alleviating memory deficits of AD model mice. Our study suggests that VPA may be beneficial in the prevention and treatment of AD.

scholarly journals Alzheimer's Disease, Cerebrovascular Disease, and the β-amyloid Cascade

2012 ◽  
Vol 39 (6) ◽  
pp. 712-728 ◽  
Author(s):  
Kie Honjo ◽  
Sandra E. Black ◽  
Nicolaas P. L. G. Verhoeff
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrovascular Disease ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Amyloid Β Protein ◽  
Vascular Risk ◽  
Risk Factor Management

Alzheimer's disease (AD), considered the commonest neurodegenerative cause of dementia, is associated with hallmark pathologies including extracellular amyloid-β protein (Aβ) deposition in extracellular senile plaques and vessels, and intraneuronal tau deposition as neurofibrillary tangles. Although AD is usually categorized as neurodegeneration distinct from cerebrovascular disease (CVD), studies have shown strong links between AD and CVD. There is evidence that vascular risk factors and CVD may accelerate Aβ 40-42 production/ aggregation/deposition and contribute to the pathology and symptomatology of AD. Aβ deposited along vessels also causes cerebral amyloid angiopathy. Amyloid imaging allowsin vivodetection of AD pathology, opening the way for prevention and early treatment, if disease-modifying therapies in the pipeline show safety and efficacy. In this review, we review the role of vascular factors and Aβ, underlining that vascular risk factor management may be important for AD prevention and treatment.

scholarly journals Cerebrospinal fluid levels of the neurotrophic factor neuroleukin are increased in early Alzheimer’s disease, but not in cerebral amyloid angiopathy

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Anna M. De Kort ◽  
H. Bea Kuiperij ◽  
Daniel Alcolea ◽  
Iris Kersten ◽  
Alexandra A. M. Versleijen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Cerebral Amyloid Angiopathy ◽  
Medical Center ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Amyloid Angiopathy ◽  
Cerebral Amyloid ◽  
Neuro Inflammation

Abstract Background Neuroleukin (NLK) is a protein with neurotrophic properties and is present in a proportion of senile plaques and amyloid laden vessels. It has been suggested that NLK is part of a neuroprotective response to amyloid β-induced cell death. The aim of our study was to investigate the value of cerebrospinal fluid (CSF) NLK levels as a biomarker of vascular amyloid deposition in patients with cerebral amyloid angiopathy (CAA) and in patients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD). Methods CSF NLK levels were quantified by ELISA in CAA patients (n = 25) and controls (n = 27) and in two independent samples of aMCI patients, AD patients, and controls: (1) From the Radboud University Medical Center (Nijmegen), we included n = 19 aMCI patients, n = 40 AD patients, and n = 32 controls. (2) From the Hospital of Sant Pau (Barcelona), we included n = 33 aMCI patients, n = 17 AD patients, and n = 50 controls. Results CSF NLK levels were similar in CAA patients and controls (p = 0.95). However, we found an elevated CSF concentration of NLK in aMCI (p < 0.0001) and AD patients (p < 0.0001) compared to controls in both samples sets. In addition, we found a correlation of CSF NLK with CSF YKL-40 (age-adjusted-spearman-rank-coefficient = 0.82, p < 0.0001) in aMCI/AD patients, a well-known glial marker of neuro-inflammation. Conclusions We found that CSF NLK levels are elevated in aMCI and AD patients compared to controls, but are not increased in CAA patients. CSF NLK levels may be related to an increased neuroinflammatory state in early stages of AD, given its association with YKL-40.

scholarly journals Postmortem Neocortical 3H-PiB Binding and Levels of Unmodified and Pyroglutamate Aβ in Down Syndrome and Sporadic Alzheimer’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Violetta N. Pivtoraiko ◽  
Tamara Racic ◽  
Eric E. Abrahamson ◽  
Victor L. Villemagne ◽  
Benjamin L. Handen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Late Onset ◽  
Amyloid Β ◽  
Molecular Profile ◽  
Amyloid Angiopathy ◽  
Neuritic Plaques ◽  
Amyloid Deposits

Individuals with Down syndrome (DS) have a genetic predisposition for amyloid-β (Aβ) overproduction and earlier onset of Aβ deposits compared to patients with sporadic late-onset Alzheimer’s disease (AD). Positron emission tomography (PET) with Pittsburgh Compound-B (PiB) detects fibrillar Aβ pathology in living people with DS and AD, but its relationship with heterogeneous Aβ forms aggregated within amyloid deposits is not well understood. We performed quantitative in vitro3H-PiB binding assays and enzyme-linked immunosorbent assays of fibrillar (insoluble) unmodified Aβ40 and Aβ42 forms and N-terminus truncated and pyroglutamate-modified AβNpE3-40 and AβNpE3-42 forms in postmortem frontal cortex and precuneus samples from 18 DS cases aged 43–63 years and 17 late-onset AD cases aged 62–99 years. Both diagnostic groups had frequent neocortical neuritic plaques, while the DS group had more severe vascular amyloid pathology (cerebral amyloid angiopathy, CAA). Compared to the AD group, the DS group had higher levels of Aβ40 and AβNpE3-40, while the two groups did not differ by Aβ42 and AβNpE3-42 levels. This resulted in lower ratios of Aβ42/Aβ40 and AβNpE3-42/AβNpE3-40 in the DS group compared to the AD group. Correlations of Aβ42/Aβ40 and AβNpE3-42/AβNpE3-40 ratios with CAA severity were strong in DS cases and weak in AD cases. Pyroglutamate-modified Aβ levels were lower than unmodified Aβ levels in both diagnostic groups, but within group proportions of both pyroglutamate-modified Aβ forms relative to both unmodified Aβ forms were lower in the DS group but not in the AD group. The two diagnostic groups did not differ by 3H-PiB binding levels. These results demonstrate that compared to late-onset AD cases, adult DS individuals with similar severity of neocortical neuritic plaques and greater CAA pathology have a preponderance of both pyroglutamate-modified AβNpE3-40 and unmodified Aβ40 forms. Despite the distinct molecular profile of Aβ forms and greater vascular amyloidosis in DS cases, cortical 3H-PiB binding does not distinguish between diagnostic groups that are at an advanced level of amyloid plaque pathology. This underscores the need for the development of CAA-selective PET radiopharmaceuticals to detect and track the progression of cerebral vascular amyloid deposits in relation to Aβ plaques in individuals with DS.

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.

Biological Signatures of Alzheimer’s Disease

2020 ◽  
Vol 20 (9) ◽  
pp. 770-781 ◽  
Author(s):  
Poornima Sharma ◽  
Anjali Sharma ◽  
Faizana Fayaz ◽  
Sharad Wakode ◽  
Faheem H. Pottoo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Senile Plaque ◽  
Senile Plaques ◽  
Amyloid Deposition ◽  
Immune Defense ◽  
Amyloid Angiopathy ◽  
Microvascular Changes ◽  
Β Amyloid

Alzheimer’s disease (AD) is the most prevalent and severe neurodegenerative disease affecting more than 0.024 billion people globally, more common in women as compared to men. Senile plaques and amyloid deposition are among the main causes of AD. Amyloid deposition is considered as a central event which induces the link between the production of β amyloid and vascular changes. Presence of numerous biomarkers such as cerebral amyloid angiopathy, microvascular changes, senile plaques, changes in white matter, granulovascular degeneration specifies the manifestation of AD while an aggregation of tau protein is considered as a primary marker of AD. Likewise, microvascular changes, activation of microglia (immune defense system of CNS), amyloid-beta aggregation, senile plaque and many more biomarkers are nearly found in all Alzheimer’s patients. It was seen that 70% of Alzheimer’s cases occur due to genetic factors. It has been reported in various studies that apolipoprotein E(APOE) mainly APOE4 is one of the major risk factors for the later onset of AD. Several pathological changes also occur in the white matter which include dilation of the perivascular space, loss of axons, reactive astrocytosis, oligodendrocytes and failure to drain interstitial fluid. In this review, we aim to highlight the various biological signatures associated with the AD which may further help in discovering multitargeting drug therapy.

scholarly journals NLRP3 Inflammasome: A Starring Role in Amyloid-β- and Tau-Driven Pathological Events in Alzheimer’s Disease

2021 ◽  
pp. 1-22
Author(s):  
Mariana Van Zeller ◽  
Diogo M. Dias ◽  
Ana M. Sebastião ◽  
Cláudia A. Valente
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glial Cells ◽  
Neurofibrillary Tangles ◽  
Nlrp3 Inflammasome ◽  
Neuronal Death ◽  
Inflammatory Responses ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Wide Range

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease commonly diagnosed among the elderly population. AD is characterized by the loss of synaptic connections, neuronal death, and progressive cognitive impairment, attributed to the extracellular accumulation of senile plaques, composed by insoluble aggregates of amyloid-β (Aβ) peptides, and to the intraneuronal formation of neurofibrillary tangles shaped by hyperphosphorylated filaments of the microtubule-associated protein tau. However, evidence showed that chronic inflammatory responses, with long-lasting exacerbated release of proinflammatory cytokines by reactive glial cells, contribute to the pathophysiology of the disease. NLRP3 inflammasome (NLRP3), a cytosolic multiprotein complex sensor of a wide range of stimuli, was implicated in multiple neurological diseases, including AD. Herein, we review the most recent findings regarding the involvement of NLRP3 in the pathogenesis of AD. We address the mechanisms of NLRP3 priming and activation in glial cells by Aβ species and the potential role of neurofibrillary tangles and extracellular vesicles in disease progression. Neuronal death by NLRP3-mediated pyroptosis, driven by the interneuronal tau propagation, is also discussed. We present considerable evidence to claim that NLRP3 inhibition, is undoubtfully a potential therapeutic strategy for AD.

A theoretical study on the molecular determinants of the affibody protein ZAβ3bound to an amyloid β peptide

2015 ◽  
Vol 17 (26) ◽  
pp. 16886-16893 ◽  
Author(s):  
Xu Wang ◽  
Xianqiang Sun ◽  
Guanglin Kuang ◽  
Hans Ågren ◽  
Yaoquan Tu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Theoretical Study ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Aβ Peptides ◽  
Molecular Determinants

The investigation of the (ZAβ3)2:Aβ complex highlights the energetic contribution of affibody residues to the binding with alzheimer's disease associated Aβ peptides.

scholarly journals Gallium nanoparticles as novel inhibitors of Aβ40 aggregation

2021 ◽  
Author(s):  
Rolando Oyola ◽  
Deguo Du ◽  
Idalia Ramos ◽  
Kyabeth Torres ◽  
Ambar S Delgado ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Aβ Peptides ◽  
Gallium Nanoparticles

Alzheimer’s disease (AD) has been consistently related to the formation of senile amyloid plaques mainly composed of amyloid β (Aβ) peptides. The toxicity of Aβ aggregates has been indicated to...

scholarly journals Dimensional Changes in Lipid Rafts from Human Brain Cortex Associated to Development of Alzheimer’s Disease. Predictions from an Agent-Based Mathematical Model

2021 ◽  
Vol 22 (22) ◽  
pp. 12181
Author(s):  
Guido Santos ◽  
Mario Díaz
Keyword(s):  
Alzheimer’S Disease ◽  
Mathematical Model ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Lipid Rafts ◽  
Brain Cortex ◽  
Clinical Symptoms ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Human Brain Cortex

Alzheimer’s disease (AD) is a neurodegenerative disease caused by abnormal functioning of critical physiological processes in nerve cells and aberrant accumulation of protein aggregates in the brain. The initial cause remains elusive—the only unquestionable risk factor for the most frequent variant of the disease is age. Lipid rafts are microdomains present in nerve cell membranes and they are known to play a significant role in the generation of hallmark proteinopathies associated to AD, namely senile plaques, formed by aggregates of amyloid β peptides. Recent studies have demonstrated that human brain cortex lipid rafts are altered during early neuropathological phases of AD as defined by Braak and Braak staging. The lipid composition and physical properties of these domains appear altered even before clinical symptoms are detected. Here, we use a coarse grain molecular dynamics mathematical model to predict the dimensional evolution of these domains using the experimental data reported by our group in human frontal cortex. The model predicts significant size and frequency changes which are detectable at the earliest neuropathological stage (ADI/II) of Alzheimer’s disease. Simulations reveal a lower number and a larger size in lipid rafts from ADV/VI, the most advanced stage of AD. Paralleling these changes, the predictions also indicate that non-rafts domains undergo simultaneous alterations in membrane peroxidability, which support a link between oxidative stress and AD progression. These synergistic changes in lipid rafts dimensions and non-rafts peroxidability are likely to become part of a positive feedback loop linked to an irreversible amyloid burden and neuronal death during the evolution of AD neuropathology.

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