Article
Evidence of Alzheimer-related pathology in aged rats with kaolin-induced hydrocephalus
Nachweis von Alzheimerpathologie bei alternden Ratten mit Kaolin-induziertem Hydrozephalus
Search Medline for
Authors
Published: | April 11, 2007 |
---|
Outline
Text
Objective: 30-50% of shunted normal pressure hydrocephalus patients show amyloid (A-beta) plaques and neurofibrillary tangles, consistent with Alzheimer’s disease (AD), on cortical biopsy. Decreased A-beta clearance via cerebrospinal fluid (CSF) and vascular endothelium at the blood-brain barrier (BBB) may be causative. We investigated A-beta accumulation, A-beta transport and TAU pathology in aged hydrocephalic rat brains.
Methods: Kaolin-hydrocephalus was induced in 12 months old Sprague-Dawley rats (n=15). Untreated age-matched rats served as controls (n=5). A-beta and hyper-phosphorylated tau (hpTau) accumulation was investigated by specific A-beta40, A-beta42 and hpTau (pT231 and AT100) antibody immunohistochemistry performed 2, 6 and 10 weeks after hydrocephalus induction. The expression of two specific BBB-endothelial A-beta receptors was assessed by immunohistochemistry, RT-PCR and Western blotting: LRP-1, which transports A-beta out of, and RAGE, which transports A-beta into the central nervous system.
Results: In hydrocephalus, both A-beta 42 and A-beta 40 staining show increased cortical and subcortical endothelial and perivascular A-beta accumulations. At 6 and 10 weeks, parenchymal, neuronal and cortical vascular A-beta accumulations were pronounced. Also staining of hpTau showed a progressive increase in both intra- and extracellular locations. Extracellular staining of paired-helical-filament (PHF) TAU AT100 occurred in the hippocampus at 6 weeks. However, in the larger cortical pyramidal neurons, migration of hyperphosphorylated pre-tangle TAU (pT231) from neuronal dendrites to the soma occurred, as seen in AD. LRP expression was markedly decreased in cortical and hippocampal microvessels, most prominent after 6 weeks. RAGE expression showed changes opposite to LRP-1.
Conclusions: In our model, vascular and interstitial A-beta and neuronal hpTau antibody staining increased the longer the hydrocephalus persisted. In addition to the disturbed clearance via CSF in hydrocephalus, the altered endothelial receptor expressions indicated impairment of A-beta clearance mechanisms through the vascular route. A-beta does accumulate in hydrocephalus and may lead to hpTau formations, which have been shown to be involved in the fibrillogenic process in AD. This raises evidence towards a common pathophysiology underlying both diseases, AD and Normal pressure hydrocephalus.