Abstract TMP109: Bidirectional Influence Between Vascular β-amyloid and Tau: An Experimental Evidence
Background and Purpose: Cerebral amyloid angiopathy (CAA) is a putative substrate of vascular cognitive impairment and is frequently observed in Alzheimer’s disease (AD) in addition to parenchymal β-amyloid (Aβ) plaques and neurofibrillary tau tangles. Several studies using amyloid precursor protein (APP) and microtubule-associated protein tau (MAPT) bigenic mice showed enhanced neurofibrillary degeneration without any alterations in Aβ plaques, indicating that tau is downstream of Aβ. However, interaction between CAA and tau still remains unknown.
Methods: We have developed a double transgenic mouse by crossing mice overexpressing the human APP gene with Swedish-Dutch-Iowa mutations (Tg-SwDI mice) with Tg-P301S mice carrying the human MAPT gene with P301S mutation to investigate the role of CAA in tau metabolism.
Results: Immunohistochemical staining showed that the amount of total tau, 4 repeat tau, and hyperphosphorylated tau was more abundant in the double Tg mice than Tg-P301S mice. The double Tg mice showed most prominent tau accumulation in the subiculum where vascular Aβ deposition first appears in Tg-SwDI mice while they exhibited significantly increased vascular Aβ deposition in the dentate gyrus where tau accumulation is marked in Tg-P301S mice. The Aβ deposits were composed of Aβ40 and mainly observed in the capillaries. The double Tg mice showed more pronounced astrogliosis, microgliosis, and neuronal loss than wild type mice or single Tg mice with the greatest reduction of cerebral blood flow in cortex based on laser speckle flowmetry and significantly impaired spatial reference memory in the Barnes maze test.
Conclusions: These findings indicate bidirectional influence between vascular Aβ and tau, suggesting a positive feedforward loop of toxic protein accumulation. Thus, CAA plays a key role in development of dementia, both of vascular and neurodegenerative origin.
Author Disclosures: M. Ihara: None. S. Saito: None. Y. Hattori: None. Y. Yamamoto: None. K. Nagatsuka: None.
- © 2016 by American Heart Association, Inc.