Ic‐p‐018: Decoupling App Expression From Plaque: Effects of Overexpression of Appswind, Presence of Plaque, and Role of Herpes Virus
Year: 2019
Type: article
Abstract: One of the biological roles of amyloid precursor protein (APP), precursor to Abeta plaques, is to attach cargo to motors for axonal transport along microtubules. We identified a 15-aa domain in APP that is sufficient to attach kinesin-1 to fluorescent nano-beads. We also reported that transport is decreased in mice when the APP gene is knocked-out. In old transgenic mice expressing human APP, linked to Familial Alzheimer's Disease (FAD), which displays both over-expression of mutated APP and Abeta plaques, axonal transport is altered, as detected by time-lapse manganese-enhanced magnetic resonance imaging (MEMRI) in living mouse brains. Herpes simplex virus (HSV), a predicted risk factor for AD, interacts with the APP-transport system during infectious particle egress, suggesting a possible link between HSV and AD is mediated by dysfunction of the APP transport system. Using the Tet-off system to control APP expression, we decoupled expression of APP from presence of plaques in three groups of transgenic mice (APP + plaque, only plaque, and only APP) by turning APP off with doxycyclin. We measured transport rates using time-lapse MEMRI captured in an 11.7T Bruker scanner before and at successive time points after stereotactic injection of Mn (3-5nL) into CA3 of the hippocampus. Images of multiple individuals were aligned, and processed, with statistical parametric mapping (SPM) and region of interest intensity analysis. After imaging, brains were harvested for biochemistry or histopathology. We further explored whether HSV suspected of being a risk factor for AD, altered APP expression in the human brain, by examining 44 post-mortem brains of HSV encephalitis victims in sections stained for HSV and APP. APP expression increased the rate of distal accumulation of Mn, whereas plaque decreased the rate and altered proximal destinations. APP, expressed 3.2-fold over mouse APP, was suppressed with doxycycline. As previously reported in cell culture, HSV up-regulated APP in infected neurons both in the trigeminal ganglion and in the human brain. Together these results suggest that up-regulation of APP induced by infectious agents such as HSV may lead to altered axonal transport and plaque formation, thereby influencing mental processes. Supported NS062184 and MH096093.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2980861133