Accumulation of abnormally phosphorylated τ precedes the formation of neurofibrillary tangles in Alzheimer's disease

Neurofilament phosphoforms: surrogate markers for axonal injury, degeneration and loss.

1. Intracellular recordings were made in dorsal root ganglia in vitro at 37 degrees C. The L4, L5 and L6 ganglia from 46- to 51-day-old female Wistar rats were used. In each neuron conduction velocity (CV) was measured and fluorescent dye was injected. Later the intensity of the immunoreactivity to RT97 (a monoclonal antibody to the phosphorylated 200 kDa neurofilament subunit) as well as the cell size (cross-sectional area at the nuclear level) were measured in the dye-injected neurons. RT97 was used to distinguish between the L (light, neurofilament-rich) and the SD (small dark, neurofilament-poor) neuronal somata. 2. Neurons were classified as C neurons (CV less than 1.3 m/s), C/A delta neurons (1.3-2 m/s), A delta neurons (2-12 m/s) or A alpha/beta neurons (greater than 12 m/s). 3. All A-fibre somata were RT97 positive (L) and all C-fibre somata were RT97 negative (SD), although in the C/A delta group both positive and negative neurons were seen. Thus, RT97-negative somata had C (unmyelinated) or C/A delta fibres, while RT97-positive somata had A (myelinated) or C/A delta fibres. 4. The size distributions of A neurons and C neurons were consistent with their classification as L- and SD-cell neurons respectively. The size distribution of A delta cells was skewed with a peak of small cells and a tail of medium-sized cells. 5. There was a loose positive correlation between cell size and fibre CV. 6. RT97 intensity was positively correlated with CV if all neurons were considered together, but no correlation was seen within the C, A delta or A alpha/beta CV groups. 7. RT97 intensity was positively correlated with cell size when all neurons were considered together. Although no correlation was seen within the C or the A delta CV groups, a clear positive correlation was seen for A alpha/beta neurons. 8. The relationship of RT97 intensity to cell size was not demonstrably altered by axotomy, time in vitro or the presence of intracellular dye in control experiments. 9. RT97-negative and -positive neurons could be seen in neonatal rat ganglia. Their size distributions resembled, respectively, the SD- and L-neuron populations at this age. RT97 immunoreactivity may therefore be a useful predictor of the cell type and myelinated state which a sensory cell is destined to reach in the adult rat.

Soma neurofilament immunoreactivity is related to cell size and fibre conduction velocity in rat primary sensory neurons.

A monoclonal antibody (HK-249) that recognizes a glucosamine sulfate alpha 1----4 glucuronic acid-containing determinant in heparan sulfate (HS) chains of a basement membrane-derived heparan sulfate proteoglycan identified and immunolocalized HS specifically to the amyloid deposits in neuritic plaques (NPs), congophilic angiopathy (CA), as well as in neurofibrillary tangles (NFTs) and non-tangle-bearing neurons in the brains of Alzheimer's and Down's syndrome (DS) patients. Ultrastructural immunohistochemistry demonstrated that HS within neurons of Alzheimer's disease (AD) brain was localized to lipofuscin granules, an aging pigment previously shown also to contain beta-amyloid protein (BAP). Heparan sulfate also was localized to neurite-containing, nonfibrillar 'primitive' plaques that also demonstrated positive BAP immunoreactivity in both AD and DS brains. Antibodies to laminin, fibronectin, and a chondroitin sulfate proteoglycan failed to show positive immunostaining of the HS-containing sites described above. Analysis of DS patients at different ages revealed that HS accumulated within neurons of the hippocampus and amygdala as early as 1 day after birth. Young age-matched controls did not demonstrate similar positive HS immunoreactivity in neurons, whereas positive immunostaining for HS was observed in other regions thought to normally contain HS. The earliest deposition of BAP was first observed as 'amorphous' or 'diffuse' cortical deposits in DS brain in patients aged 18 and 24 years before the accumulation of fibrillar amyloid (observed in DS patients who are 35 years and older). These cortical deposits also contained positive HS immunoreactivity, implying that HS accumulation in conjunction with the BAP is an early event that ultimately may contribute to the early age-related accumulation (ie, as early as 35 years of age in DS) of NPs, NFTs, and/or CA. Furthermore the colocalization of HS and BAP in a number of specific locales in AD and DS brain indicates a possible interaction between these two macromolecules that may be important in lesion development in these two diseases.

Early accumulation of heparan sulfate in neurons and in the beta-amyloid protein-containing lesions of Alzheimer's disease and Down's syndrome.

Hippocampal and neocortical ubiquitin-immunoreactive inclusions in amyotrophic lateral sclerosis with dementia.

Three monoclonal antibodies to neurofilaments (RT97, BF10 and 147), two of which also recognised neurofibrillary tangles (RT97 and BF10), have all been shown to be specific for phosphorylated epitopes. Treatment of histological sections with alkaline phosphatase prior to immunostaining resulted in reduction of axonal neurofilament staining with all three whilst the neurofibrillary tangles staining with BF10 was unaffected. Antibody 147 was found to recognise weakly some neurofibrillary tangles following alkaline phosphatase treatment. The results presented confirm the presence of structurally abnormal but phosphorylated neurofilaments in neurofibrillary tangles.

https://jnnp.bmj.com/content/jnnp/49/11/1213.full.pdf

Alzheimer neurofibrillary tangles contain phosphorylated and hidden neurofilament epitopes.

Dementia of the Alzheimer type (ATD), both presenile and senile, has a characteristic brain histopathology comprising neurofibrillary tangles (NFT), senile plaques, granulovacuolar bodies and Hirano bodies. Alzheimer-type NFT are also found in several other diseases, including Down’s syndrome, postencephalitic Parkinson’s disease, dementia pugilistica, subacute sclerosing panencephalitis, Parkinson-dementia complex and Hallevorden-Spatz syndrome (Wisniewski et al. 1979). In ATD, NFT are found in certain cortical and subcortical neuronal perikarya and consist of aggregates of abnormal fibres.

The Nature of Neurofibrillary Tangles

Alzheimer neurofibrillary tangles contain phosphorylated and hidden neurofilament epitopes

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Alzheimer neurofibrillary tangles contain phosphorylated and hidden neurofilament epitopes.

The Nature of Neurofibrillary Tangles

Alzheimer neurofibrillary tangles contain phosphorylated and hidden neurofilament epitopes