Oral and subcutaneous administration of the glycosaminoglycan C3 attenuates Aβ(25–35)-induced abnormal tau protein immunoreactivity in rat brain

• Published in: Neurobiology of aging Vol. 23; no. 1; pp. 97 - 104
• Main Authors: Dudas, B, Cornelli, U, Lee, J.M, Hejna, M.J, Walzer, M, Lorens, S.A, Mervis, R.F, Fareed, J, Hanin, I
• Format: Journal Article
• Language: English
• Published: London Elsevier Inc 2002; Elsevier Science
• Subjects: Alzheimer’s disease; Amyloid; Animal model; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Glycosaminoglycan; Medical sciences; Neurology; Proteoglycan; Tau protein; Proteoglycan; Animal model; Glycosaminoglycan; Amyloid; Tau protein; Alzheimer’s disease; Nervous system diseases; Rat; Alzheimer disease; Rodentia; Central nervous system; Oral administration; Cerebral disorder; Encephalon; Vertebrata; Mammalia; β Amyloid protein; Central nervous system disease; Subcutaneous administration; Degenerative disease; Alzheimer's disease
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/S0197-4580(01)00255-X

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-β (Aβ), 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 Aβ(25–35). Oral administration of C3 (25 mg/kg; once daily) was initiated 3 days prior to Aβ(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, Aβ(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 Aβ(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.