title: Kaolin-induced chronic hydrocephalus accelerates amyloid deposition and vascular disease in transgenic rats expressing high levels of human APP.
abstract: BACKGROUND
  Normal pressure hydrocephalus (NPH) is most common in the elderly and has a high co-morbidity with Alzheimer's disease (AD) and cerebrovascular disease (CVD). To understand the relationship between NPH, AD and CVD, we investigated how chronic hydrocephalus impacts brain amyloid-beta peptide (Aβ) accumulation and vascular pathology in an AD transgenic rodent model. Previously we showed that the altered CSF physiology produced by kaolin-hydrocephalus in older wild-type Sprague-Dawley rats increased Aβ and hyperphosphorylated Tau (Silverberg et. al. Brain Res. 2010, 1317:286-296). We postulated that hydrocephalus would similarly affect an AD rat model.
  
  
  METHODS
  Thirty-five transgenic rats (tgAPP21) that express high levels of human APP and naturally overproduce Aβ40 were used. Six- (n = 7) and twelve-month-old (n = 9) rats had hydrocephalus induced by cisternal kaolin injection. We analyzed Aβ burden (Aβ40, Aβ42 and oligomeric Aβ) and vascular integrity (Masson trichrome and Verhoeff-Van Gieson) by immunohistochemistry and chemical staining at 10 weeks (n = 8) and 6 months (n = 5) post hydrocephalus induction. We also analyzed whether the vascular pathology seen in tgAPP21 rats, which develop amyloid angiopathy, was accelerated by hydrocephalus. Age-matched naïve and sham-operated tgAPP21 rats served as controls (n = 19).
  
  
  RESULTS
  In hydrocephalic tgAPP21 rats, compared to naïve and sham-operated controls, there was increased Aβ 40 and oligomeric Aβ in hippocampal and cortical neurons at 10 weeks and 6 months post-hydrocephalus induction. No dense-core amyloid plaques were seen, but diffuse Aβ immunoreactivity was evident in neurons. Vascular pathology was accelerated by the induction of hydrocephalus compared to controls. In the six-month-old rats, subtle degenerative changes were noted in vessel walls at 10 weeks post-kaolin, whereas at six months post-kaolin and in the 12-month-old hydrocephalic rats more pronounced amyloid angiopathic changes were seen, with frequent large areas of infarction noted.
  
  
  CONCLUSIONS
  Kaolin-hydrocephalus can accelerate intraneuronal Aβ40 accumulation and vascular pathology in tgAPP21 rats. In addition, disrupted CSF production and reduced CSF turnover results in impaired Aβ clearance and accelerated vascular pathology in chronic hydrocephalus. The high co-morbidity seen in NPH, AD and CVD is likely not to be an age-related coincidence, but rather a convergence of pathologies related to diminished CSF clearance.
authors: Department of Neurosurgery, The Warren Alpert Medical School of Brown University and the Aldrich Laboratories at Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903 USA ; Stanford University, 710 Frenchmans Rd, Stanford, CA 94305 USA.
authors: Gerald D
authors: GD
authors: Silverberg
authors: Department of Neurosurgery, The Warren Alpert Medical School of Brown University and the Aldrich Laboratories at Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903 USA.
authors: Miles C
authors: MC
authors: Miller
authors: Department of Neurosurgery, The Warren Alpert Medical School of Brown University and the Aldrich Laboratories at Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903 USA.
authors: Crissey L
authors: CL
authors: Pascale
authors: Department of Neurosurgery, The Warren Alpert Medical School of Brown University and the Aldrich Laboratories at Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903 USA.
authors: Ilias N
authors: IN
authors: Caralopoulos
authors: Department of Veterinary Pathobiology, University of Missouri College of Veterinary Medicine, Columbia, MO 65211 USA.
authors: Yuksel
authors: Y
authors: Agca
authors: Department of Veterinary Pathobiology, University of Missouri College of Veterinary Medicine, Columbia, MO 65211 USA.
authors: Cansu
authors: C
authors: Agca
authors: Department of Neurosurgery, The Warren Alpert Medical School of Brown University and the Aldrich Laboratories at Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903 USA ; Department of Pathology (Neuropathology), Warren Alpert Medical School of Brown University and the Aldrich Laboratories at Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903 USA.
authors: Edward G
authors: EG
authors: Stopa
keywords: Amyloid angiopathy; Amyloid-beta peptide; CSF circulation; Cerebrovascular disease; Kaolin-induced hydrocephalus; Normal pressure hydrocephalus; Solute clearance; Transgenic rat