QUANTITATIVE IMAGE-ANALYSIS OF TEMPORAL CHANGES IN TAU-PROTEIN AND NEUROFILAMENT-PROTEIN DURING THE COURSE OF ACUTE EXPERIMENTAL NEUROFIBRILLARY DEGENERATION - NONPHOSPHORYLATED EPITOPES PRECEDE PHOSPHORYLATION
J. Savory et al., QUANTITATIVE IMAGE-ANALYSIS OF TEMPORAL CHANGES IN TAU-PROTEIN AND NEUROFILAMENT-PROTEIN DURING THE COURSE OF ACUTE EXPERIMENTAL NEUROFIBRILLARY DEGENERATION - NONPHOSPHORYLATED EPITOPES PRECEDE PHOSPHORYLATION, Brain research, 707(2), 1996, pp. 272-281
Perturbation of the neuronal cytoskeleton represents an integral featu
re of neurofibrillary tangles which are characteristic neuropathologic
al findings seen in Alzheimer's disease. Microtubule associated protei
n tau (tau) is considered to be the major component of these lesions a
lthough neurofilament proteins also are present. The present study exp
lores the formation of intraneuronal tan and neurofilament protein agg
regates using intracisternal administration of aluminum maltolate to r
abbits. The time course of the formation of these aggregates and subse
quent phosphorylation have been investigated by immunohistochemical me
thods using a panel of monoclonal antibodies, with quantitation of the
staining by image analysis. Neurofilament proteins begin to aggregate
by day 1 following aluminum maltolate injection on day 0. Increases i
n non-phosphorylated neurofilament proteins are observed first, with p
hosphorylated epitopes being recognized by day 3. Tau follows a simila
r pattern in that non-phosphorylated epitopes appear to precede phosph
orylation. The monoclonal antibody Alz-50 which recognizes a phosphory
lation-independent epitope of tau in Alzheimer's disease paired helica
l filaments, demonstrates positivity in the aluminum maltolate-treated
rabbits by day 3. Other tau monoclonal antibodies which recognize pho
sphorylated tau in paired helical filaments (AT8 and PHF-1) show posit
ive immunostaining on days 6-8. These results indicate that intraneuro
nal aggregation of cytoskeletal proteins can be initiated by factors o
ther than phosphorylation. However, phosphorylation occurring as a sec
ondary event probably contributes to stabilization of the aggregates.