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Biochemical Markers for Alzheimer Disease as Reflection of the Neuropathology in Cerebrospinal Fluid:
Published in Robert E. Becker, Ezio Giacobini, Alzheimer Disease, 2020
C. Bancher, H.M. Wisniewski, P.D. Mehta, K.S. Kim, I. Grundke-Iqbal, K. Iqbal
Preparations of biochemically isolated PHF have been used to immunize mice and to generate hybridomas producing monoclonal antibodies (mAbs) to PHF (Wang et al. 1984). By immunohisto-chemistry, these mAbs strongly label the NFT, NP and diffuse neuropil tangles (neuropil threads) in AD brain tissue. In cases with severe pathology, most of the staining is accounted for by the presence of a dense network of innumerable neuropil threads. The mAbs also stain isolated NFT, both before and after repeated treatment with boiling SDS. Since mAb 5-25 and 3-39 consistently stain the highest number of NFT, these two mAbs have been selected for further studies. By immune electron microscopy of negatively stained isolated PHF, it has been confirmed that the immunoreactivity resides on the PHF themselves and that it is not sensitive to treatment of the sample with a proteolytic enzyme (Merz et al. 1986; Wrzolek et al. 1987). The fact that the immunoreactivity is not abolished even after harsh treatments with detergents and proteases suggests that the mAbs are indeed directed against polypeptides tightly associated with the PHF and not against non-specific proteins trapped in the NFT or adhering to the PHF. On Western blots of isolated PHF, both mAbs label PHF polypeptides with molecular weights between 45 and 62 kDa (Grundke-Iqbal et al. 1985), similarly to those seen with rabbit antisera to PHF and with antibodies to tau (Grundke-Iqbal et al. 1986a,b). However, they do not react with tau from normal human brain or the abnormally phosphorylated tau present in unpolymerized form in the cytosol fraction of AD brain.
Neuropathology of Alzheimer’s disease
Published in Howard H. Feldman, Atlas of Alzheimer's Disease, 2007
Neuropil threads are another form of neurofibrillary degeneration in which PHF accumulates in distal dendrites and axons. These short thread-like structures have the same staining characteristics as NFTs and are widely distributed throughout the gray matter in AD (Figure 5.8d). As mentioned above, some of the dystrophic neurites of senile plaques also contain PHFs.
Degenerative Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James A. Mastrianni, Elizabeth A. Harris
Five cellular features are present: Glial cytoplasmic inclusions (GCIs) containing alpha-synuclein filaments in oligodendroglia: the most characteristic cellular pathology (Figure 16.55).29Widely distributed, more common in white matter than gray matter, more common in motor fibers than sensory fibers, and may be flame- or sickle-shaped.Ultrastructurally, they are randomly arranged tubules or filaments, of diameter 20–40 nm, and associated with granular material.They are present in the brains of all cases of MSA (i.e. 100% sensitivity) but not all brains containing GCIs are from patients with MSA (i.e. < 100% specificity).They are also found in CBD, PSP, SCA1, and chromosome 17–linked dementia.Neuronal cytoplasmic inclusions.Neuronal nuclear inclusions.Glial nuclear inclusions.Neuropil threads.
Stereotaxic-assisted gene therapy in Alzheimer’s and Parkinson’s diseases: therapeutic potentials and clinical frontiers
Published in Expert Review of Neurotherapeutics, 2022
Samar O. El Ganainy, Tony Cijsouw, Mennatallah A. Ali, Susanne Schoch, Amira Sayed Hanafy
Being the major cause of dementia, AD incidence is rising and projected to affect over 130 million people by 2050 worldwide [43]. Its etiology is rather a complex interplay between genetic and environmental factors. However, its fundamental pathologic pathways remain unclear as some recent clinical trials based on traditional AD hypotheses were unsuccessful [44]. AD is characterized by two major anatomical observations: beta-amyloid (Aβ) plaques in the brain parenchyma and neurofibrillary tangles (NFTs) in neuronal axons. Aβ plaques are extracellular aggregates of Aβ peptides of predominately 40 and 42 amino acids of length (Aβ40 and Aβ42, respectively) that are the proteolytic metabolites of the integral membrane protein amyloid precursor protein (APP) [45]. APP is proteolytically cleaved in a two-step process, first by β-secretase (or β-site APP cleaving enzyme-1, BACE1) and finally by γ-secretases. It is thought that an increased Aβ42/Aβ40 molar ratio leads to the formation of amyloid plaques [46]. Unlike amyloid plaques, NFTs are closely related to dementia [47]. In AD, neuropil threads, consisting primarily of aggregated tau fibrils, precipitate within the neurons in a stereotypic spatiotemporal manner [47]. Hyperphosphorylated tau associates into tangles within the axonal cytoplasm, disrupting axon structure and function. Besides, the severe loss of chemical neuronal synapses, most obvious at late stages, is an additional AD hallmark [48].
Exposure to pyrethroids induces behavioral impairments, neurofibrillary tangles and tau pathology in Alzheimer’s type neurodegeneration in adult Wistar rats
Published in Drug and Chemical Toxicology, 2022
K. A. Iteire, A. T. Sowole, B. Ogunlade
Amyloid beta (Aβ or A-beta) denotes peptides of 36 – 43 amino acids that have been observed to be crucially involved in AD prognosis and as the major component of amyloid plaques found in the brains of Alzheimer patients (Hamley 2012). In AD and family of other related neurodegenerative diseases, called tauopathies, tau protein is abnormally hyperphosphorylated and aggregated into bundles of filaments (Grundke-Iqbal et al.1986). Tau pathology presents as intraneuronal neurofibrillary tangles of Paired Helical Filaments (PHF) sometimes admixed with Straight Filaments (SF) in AD brain. Aggregations of abnormally hyperphosphorylated filaments are also observed in dystrophic neuritis surrounding the β-amyloid plaque core and in the neuropilas neuropil threads (Braak et al.1986). Neurofibrillary degeneration of abnormally hyperphosphorylated tau is apparently required for the clinical diagnosis of AD and related tauopathies which can be studied by using immunohistochemical methods (Tomlinson et al.1970, Alafuzoff et al.1987, Arriagada et al.1992).
The diagnosis of progressive supranuclear palsy: current opinions and challenges
Published in Expert Review of Neurotherapeutics, 2018
The 1996 NINDS neuropathological criteria for PSP require tau immunoreactive globose neurofibrillary tangles and neuropil threads in the brainstem and basal ganglia for diagnosis of definite PSP [2]. Characteristic lesions are composed of tau isoform harboring 4 microtubule-binding repeat motifs (4R tau) forming straight filaments as opposed to paired helical filaments in AD [47]. Atrophy of the frontal convexity, subthalamic nucleus, and midbrain as well as depigmentation of substantia nigra and other brainstem nuclei occurs but is not specific to PSP. Severity of astrogliosis and neuronal loss appears to correlate with burden of neurofibrillary tangles primarily affecting the basal ganglia, subthalamic nucleus, ocular motor and trochlear nuclei, periaqueductal gray, and the cortex to a variable extent [2]. Typical lesions also include tau immunoreactive-coiled bodies in oligodendroglia and tufted astrocytes [48]. Neuropil threads, axonal spheroids, and demyelination are seen as a result of axonal and dendritic tau pathology [49]. Histopathological findings are distinct from CBD, another 4R tauopathy characterized by ballooned neurons, astrocytic plaques, and potentially greater cortical involvement [48].