Aberrant neurofilament phosphorylation in Alzheimer disease.

Abstract

Alzheimer tangles, despite their location in neuronal perikarya, react immunocytochemically with monoclonal antibodies to phosphorylated epitopes of neurofilaments. Normal perikarya do not contain phosphorylated neurofilaments. The aberrant phosphorylation in both plaques and tangles seems to be largely restricted to individual phosphorylation sites among the many sites available in neurorilaments. It is suggested that the Alzheimer lesion involves an imbalance within specific kinases responsible for phosphorylation of different sites in neurofilaments. Subsequent studies have shown (3) that the macroheterogeneity was posttranslational and depended on phosphorylation. Thus, antibodies from group II reacted exclusively with phosphorylated neurofilaments; those ofgroup III, with nonphosphorylated epitopes in neurofilaments that are masked by phosphorylation; and antibodies from group IV, apparently with a more accessible, nonphosphorylated neurofilament epitope. In tissue sections, trypsin or phosphatase treatment alone had no effect on the immunocytochemical staining by antibodies from group II. However, trypsin followed by phosphatase reduced the staining. Trypsin treatment abolished the staining by antibodies from group III. However, the staining with these antibodies reappeared by subsequent phosphatase treatment but was converted to axonal staining-i.e., from a group III to a group II pattern. The data permitted the conclusions that neurofilaments in dendrites, perikarya, and proximal axons are nonphosphorylated and that phosphorylation occurs during transport along the axon. Furthermore, it was apparent that phosphorylated neurofilaments were more compact than nonphosphorylated forms.Alzheimer tangles are perikaryonal constituents. They have been shown by Selkoe et al. (4) to differ from normal neurofilaments in their resistance to solubilization by even extensive treatment with sodium dodecyl sulfate and, thus, can be considered highly compacted structures at least with regard to tertiary conformation. In contrast, normal perikaryonal neurofilaments, which are not phosphorylated, seem, according to our data, of noncompact configuration. It appeared, therefore, of interest to study phosphorylation of Alzheimer tangles and plaques and to examine the compactness of these structures with regard to susceptibility to dephosphorylation. MATERIALS AND METHODSThis study includes two cases of Alzheimer disease, one case of Down syndrome, and a case of cerebral infarct. The first three cases exhibited progressive dementia and revealed, on autopsy, severe changes of the Alzheimer type in hippocampus and neocortex. The last case had only few changes of the Alzheimer type.Paraffin sections were stained immunocytochemically (5) by using monoclonal first-layer antibodies, goat anti-mouse 4274 The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Sigma-1 receptor regulates Tau phosphorylation and axon extension by shaping p35 turnover via myristic acid

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Processing of Alzheimer beta/A4 amyloid precursor protein: modulation by agents that regulate protein phosphorylation.

“…Abnormalities of protein phosphorylation are characteristic of AD (2)(3)(4)(5). Two components of neurofibrillary tangles, the microtubule-associated protein tau and neurofilament proteins, are abnormally phosphorylated (2,3).…”

“…Abnormalities of protein phosphorylation are characteristic of AD (2)(3)(4)(5). Two components of neurofibrillary tangles, the microtubule-associated protein tau and neurofilament proteins, are abnormally phosphorylated (2,3). Moreover, protein kinase C (PKC) activity has been reported to be altered in AD brain as well as in fibroblasts derived from patients with sporadic AD, familial AD, and Down syndrome (4,5).…”

Squid (Loligo pealei) Giant Fiber System: A Model for Studying Neurodegeneration and Dementia?

“…For many neurodegenerative disorders, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD), one of the principal neuronal pathologies is the accumulation of abnormal aggregates and neurofibrillary tangles within the cell body; these often contain, among many other proteins, extensively phosphorylated cytoskeletal proteins, such as PHF tau in AD and NFs in ALS (Sternberger et al, 1985;Lee, 1995;Julien and Mushynski, 1998;Al-Chalabi and Miller, 2003). Evidently such accumulations are toxic to cells, which accounts for the neuronal loss that leads to memory defects and dementia.…”