scholarly journals Cryo-EM structures of tau filaments from Alzheimer’s disease with PET ligand APN-1607

2021 ◽  
Vol 141 (5) ◽  
pp. 697-708
Author(s):  
Yang Shi ◽  
Alexey G. Murzin ◽  
Benjamin Falcon ◽  
Alexander Epstein ◽  
Jonathan Machin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Binding Sites ◽  
Binding Activity ◽  
Cortical Atrophy ◽  
Binding Modes ◽  
Major Site ◽  
Age Related ◽  
Positron Emission

AbstractTau and Aβ assemblies of Alzheimer’s disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs and SFs). APN-1607 (PM-PBB3) is a recently described PET ligand for AD and other tau proteinopathies. Since it is not known where in the tau folds PET ligands bind, we used electron cryo-microscopy (cryo-EM) to determine the binding sites of APN-1607 in the Alzheimer fold. We identified two major sites in the β-helix of PHFs and SFs and a third major site in the C-shaped cavity of SFs. In addition, we report that tau filaments from posterior cortical atrophy (PCA) and primary age-related tauopathy (PART) are identical to those from AD. In support, fluorescence labelling showed binding of APN-1607 to intraneuronal inclusions in AD, PART and PCA. Knowledge of the binding modes of APN-1607 to tau filaments may lead to the development of new ligands with increased specificity and binding activity. We show that cryo-EM can be used to identify the binding sites of small molecules in amyloid filaments.

Age-Associated Memory Loss: Initial Neuropsychological and Cerebral Metabolic Findings of a Longitudinal Study

1994 ◽  
Vol 6 (1) ◽  
pp. 23-44 ◽  
Author(s):  
Gary W. Small ◽  
Anna Okonek ◽  
Mark A. Mandelkern ◽  
Asenath La Rue ◽  
Linda Chang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Longitudinal Study ◽  
Cognitive Abilities ◽  
Mood State ◽  
Familial Risk ◽  
Memory Loss ◽  
Subjective Memory ◽  
Age Related ◽  
Positron Emission

To determine the relationships between clinical and brain function in persons with a familial risk for Alzheimer's disease, the authors assessed subjective and objective cognitive abilities, mood state, and cerebral glucose metabolism (using positron emission tomography) in 43 persons with age-associated memory impairment, with and without first-degree relatives with a clinical diagnosis of Alzheimer's disease. Subjective complaints of memory loss, mood state ratings, and objective memory measures were similar in persons with a family history of Alzheimer's disease (n = 29) compared to those without such a history (n = 14). Metabolic ratios in the frontal regions correlated with a decrease in a specific type of subjective memory complaint (mnemonics usage; p < .001) and some mood state ratings. These results indicate that parietal and temporal hypometabolism is not evident in persons with mild age-related memory complaints, even when such subjects have a familial risk for Alzheimer's disease. Moreover, self-reports of mnemonics usage may be sensitive indicators of decreased frontal lobe function. Longitudinal study will determine whether such clinical and metabolic measures will predict eventual disease progression.

99mTc-labeled Small Molecules for Diagnosis of Alzheimer’s Disease: Past, Recent and Future Perspectives

2019 ◽  
Vol 26 (12) ◽  
pp. 2166-2189 ◽  
Author(s):  
Sajjad Molavipordanjani ◽  
Saeed Emami ◽  
Seyed Jalal Hosseinimehr
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Early Stage ◽  
Amyloid Plaques ◽  
Design Synthesis ◽  
Future Studies ◽  
Age Related ◽  
Derivatives Of

Background: Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disease. Its prominent hallmarks are extracellular deposition of β-amyloids (amyloid plaques), intracellular neurofibrillary tangles (NTFs), neurodegeneration and finally loss of cognitive function. Hence, AD diagnosis in the early stage and monitoring of the disease are of great importance. Methods: In this review article, we have reviewed recent efforts for design, synthesis and evaluation of 99mTc labeled small molecule for AD imaging purposes. Results: These small molecules include derivatives of Congo red, benzothiazole, benzofuran, benzoxazole, naphthalene, biphenyl, chalcone, flavone, aurone, stilbene, curcumin, dibenzylideneacetone, quinoxaline, etc. The different aspects of 99mTc-labeled small molecules including chemical structure, their affinity toward amyloid plaques, BBB permeation and in vivo/vitro stability will be discussed. Conclusion: The findings of this review confirm the importance of 99mTc-labeled small molecules for AD imaging. Future studies based on the pharmacophore of these designed compounds are needed for improvement of these molecules for clinical application.

scholarly journals Alzheimer's Disease Including Focal Presentations

2019 ◽  
Vol 39 (02) ◽  
pp. 213-226 ◽  
Author(s):  
Nicolas Villain ◽  
Bruno Dubois
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Medial Temporal Lobe ◽  
Chronic Traumatic Encephalopathy ◽  
Hippocampal Sclerosis ◽  
Clinical Status ◽  
Lewy Body Disease ◽  
Epidemiological Data ◽  
Cortical Atrophy ◽  
Age Related

AbstractAlzheimer's disease (AD) is the commonest neurodegenerative disease and the most frequent cause of dementia. It affects 30 million people worldwide. Current research criteria focus on biomarkers' status for amyloid and tau using positron emission tomography and cerebrospinal fluid analysis, independent of clinical status. Current epidemiological data, which mostly rely on biomarker-undetermined AD cases, have highlighted ApoE4 and age as the main risk factors. Rare autosomal dominant mutations also account for a small fraction of early-onset AD. The main clinical phenotype at presentation is the amnestic phenotype targeting episodic memory. This is followed by rarer phenotypes such as posterior cortical atrophy, logopenic variant of primary progressive aphasia, frontal variant AD, corticobasal syndrome, and other even rarer presentations mimicking language variants of frontotemporal dementia. Main differential diagnoses include hippocampal sclerosis with TDP-43, primary age-related tauopathy, argyrophilic grain disease, frontotemporal lobar degeneration, Lewy body disease, chronic traumatic encephalopathy as well as nondegenerative disorders such as cerebrovascular disease, chronic alcohol consumption, limbic encephalitis, medial temporal lobe epilepsy, and others. Co-occurrence of AD pathology with other neurodegenerative and vascular diseases is common and increases with age. This presents a challenge in current clinical practice due to a lack of reliable biomarkers for non-AD neurodegenerative diseases.

scholarly journals 18F–THK–5351, Fluorodeoxyglucose, and Florbetaben PET Images in Atypical Alzheimer’s Disease: A Pictorial Insight into Disease Pathophysiology

2021 ◽  
Vol 11 (4) ◽  
pp. 465
Author(s):  
Sohee Park ◽  
Minyoung Oh ◽  
Jae Kim ◽  
Jae-Hong Lee ◽  
Young Yoon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Symptoms ◽  
Primary Progressive Aphasia ◽  
Clinical Findings ◽  
Cortical Atrophy ◽  
Positron Emission ◽  
Clinical Presentations ◽  
Atypical Alzheimer’S Disease ◽  
Insight Into

The recent advance of positron emission tomography (PET) tracers as biomarkers in Alzheimer’s disease (AD) provides more insight into pathophysiology, preclinical diagnosis, and further therapeutic strategies. However, synergistic processes or interactions between amyloid and tau deposits are still poorly understood. To better understand their relationship in focal brain changes with clinical phenotypes, we focused on region-specific or atypical AD characterized by focal clinical presentations: Posterior cortical atrophy (PCA) and logopenic variant of primary progressive aphasia (lpvPPA). We compared three different PET images with 18F–THK–5351 (tau), 18F–Florbetaben (amyloid beta, Aβ), and 18F–Fluorodeoxyglucose (glucose metabolism) to investigate potential interactions among pathologies and clinical findings. Whereas the amyloid accumulations were widespread throughout the neocortex, tau retentions and glucose hypometabolism showed focal changes corresponding to the clinical features. The distinctly localized patterns were more prominent in tau PET imaging. These findings suggest that tau pathology correlates more closely to the clinical symptoms and the neurodegenerative processes than Aβ pathology in AD.

SPECIFIC PROPERTIES OF TUBULIN IN THE PREFRONTAL CORTEX IN CONTROL, SCHIZOPHRENIA AND VASCULAR DEMENTIA

2020 ◽  
pp. 65-71
Author(s):  
Burbaeva G.Sh. ◽  
Androsova L.V. ◽  
Vorobyeva E.A. ◽  
Savushkina O.K.
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prefrontal Cortex ◽  
Vascular Dementia ◽  
Binding Activity ◽  
Nephelometric Method ◽  
Rate Of Polymerization ◽  
Mental Diseases ◽  
And Control ◽  
The Brain

The aim of the study was to evaluate the rate of polymerization of tubulin into microtubules and determine the level of colchicine binding (colchicine-binding activity of tubulin) in the prefrontal cortex in schizophrenia, vascular dementia (VD) and control. Colchicine-binding activity of tubulin was determined by Sherlinе in tubulin-enriched extracts of proteins from the samples. Measurement of light scattering during the polymerization of the tubulin was carried out using the nephelometric method at a wavelength of 450-550 nm. There was a significant decrease in colchicine-binding activity and the rate of tubulin polymerization in the prefrontal cortex in both diseases, and in VD to a greater extent than in schizophrenia. The obtained results suggest that not only in Alzheimer's disease, but also in other mental diseases such as schizophrenia and VD, there is a decrease in the level of tubulin in the prefrontal cortex of the brain, although to a lesser extent than in Alzheimer's disease, and consequently the amount of microtubules.

Small Molecules and Alzheimer’s Disease: Misfolding, Metabolism and Imaging

2015 ◽  
Vol 12 (5) ◽  
pp. 445-461 ◽  
Author(s):  
Viharkumar Patel ◽  
Xueli Zhang ◽  
Nicolas Tautiva ◽  
Akwe Nyabera ◽  
Opeyemi Owa ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules
Sign in / Sign up

Export Citation Format

Share Document