Oral and subcutaneous administration of the glycosaminoglycan C3 attenuates Abeta(25-35)-induced abnormal tau protein immunoreactivity in rat brain.
High molecular weight glycosaminoglycans (GAG) and proteoglycans (PG) affect pathological changes of the brain in Alzheimer's disease (AD). PG stimulate the processing and aggregation of amyloid-beta (Abeta), protect the protein from proteolysis, and increase the formation of neurofibrillary tangles by inducing the hyperphosphorylation of tau protein. These effects may be competitively inhibited by GAG. We have studied the effects of orally (by gavage) and subcutaneously (s.c.) administered low molecular weight heparin, C3 (4-10 oligosaccharides; MW = 2.1 kDa; USP value = 12 U/mg), on abnormal tau-2 protein immunoreactivity in the rat hippocampus following a single, unilateral intra-amygdaloid administration of Abeta(25-35). Oral administration of C3 (25 mg/kg; once daily) was initiated 3 days prior to Abeta(25-35) administration, and was continued daily for an additional 14 days. S.c. administration of C3 (2.5 mg/kg, twice daily), was started 3 days prior to, and was continued for 32 days after, Abeta(25-35) administration. Animal brains were subsequently processed for tau-2, ChAT-immunoreactivity, choline acetyltransferase (ChAT) activity and acetylcholinesterase (AChE) activity. Both oral and s.c. administration of C3 attenuated Abeta(25-35) induced appearance of tau-2-immunoreactive (IR) perikarya in the ipsilateral hippocampus (P < 0.05). Hippocampal cholinergic enzyme activity in C3 treated animals was not significantly different from control animals. The present findings suggest that C3 might be used successfully to prevent abnormal tau protein formation in chronic neurologic diseases, such as AD. Moreover, our data demonstrate that the mechanism of this effect does not appear to influence the cholinergic system of the brain.
Dudas
B
B
Loyola University Chicago, Stritch School of Medicine, Columbus, Ohio 43212, USA. bdudas@luc.edu
Cornelli
U
U
Lee
J M
JM
Hejna
M J
MJ
Walzer
M
M
Lorens
S A
SA
Mervis
R F
RF
Fareed
J
J
Hanin
I
I
D000110:Acetylcholinesterase / Q000378:metabolism; D000284:Administration, Oral; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007150:Immunohistochemistry; D007267:Injections; D007279:Injections, Subcutaneous; D008297:Male; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013238:Stereotaxic Techniques; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D006495:Heparin, Low-Molecular-Weight; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D016875:tau Proteins; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase