Abstract
Accumulation of beta amyloid (Aβ) in the brain is a primary feature of Alzheimer’s disease (AD) but the exact molecular mechanisms by which Aβ exerts its toxic actions are not yet entirely clear. We documented pathological changes 3 and 6 months after localised injection of recombinant, bi-cistronic adeno-associated viral vectors (rAAV2) expressing human Aβ40-GFP, Aβ42-GFP, C100-GFP or C100V717F-GFP into the hippocampus and cerebellum of 8 week old male mice. Injection of all rAAV2 vectors resulted in wide-spread transduction within the hippocampus and cerebellum, as shown by expression of transgene mRNA and GFP protein. Despite the lack of accumulation of Aβ protein after injection with AAV vectors, injection of rAAV2-Aβ42-GFP and rAAV2- C100V717F-GFP into the hippocampus resulted in significantly increased microgliosis and altered permeability of the blood brain barrier, the latter revealed by high levels of immunoglobulin G (IgG) around the injection site and the presence of IgG positive cells. In comparison, injection of rAAV2-Aβ40-GFP and rAAV2-C100-GFP into the hippocampus resulted in substantially less neuropathology. Injection of rAAV2 vectors into the cerebellum resulted in similar types of pathological changes, but to a lesser degree. The use of viral vectors to express different types of Aβ and C100 is a powerful technique with which to examine the direct in vivo consequences of Aβ expression in different regions of the mature nervous system and will allow experimentation and analysis of pathological AD-like changes in a broader range of species other than mouse.
Highlights
There is a large body of evidence suggesting that beta amyloid (Ab) accumulation in the brain may be a primary cause of Alzheimer’s disease (AD)
Injection of rAAV2 vectors expressing transgenes for human Ab40, Ab42, C100 and C100V717F into the mouse hippocampus and cerebellum resulted in wide-spread transduction in both brain regions and the development of some pathological changes characteristic of AD, most notably increased microgliosis and increased permeability of the blood brain barrier
The association between fibrillar Ab and microgliosis is further supported by the fact that the onset of gliosis in AD transgenic mice is closely linked to the onset of plaque deposition [31,32], and manipulating the amount of plaque deposition results in similar changes in the extent of microgliosis [33,34,35]
Summary
There is a large body of evidence suggesting that beta amyloid (Ab) accumulation in the brain may be a primary cause of Alzheimer’s disease (AD). It is difficult to determine the exact role of Ab in AD using the current available animal models, which are predominantly transgenic mice. It was the aim of this study to develop an alternative animal model for AD research using viral vectors to initiate localised expression of human Ab. There are many benefits associated with using viral vectors to develop animal models of disease. Viral vectors can rapidly express transgene proteins localised to desired brain regions, or even specific cell types. Viral vectors allow for the expression of multiple genes with much greater ease than in transgenic mice, a feature that is important when studying a multifactorial disease such as AD
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