Vascularization defects contribute to neuron loss in a mouse model for Alzheimer’s disease:
In Alzheimer’s disease (AD), beta-amyloid peptide plaques and tau protein spindles accumulate in neurons in the brain, and the neurons die. How and why the neurons die is not well understood, however, nor are the exact roles played by beta amyloid and tau accumulation. In fact, one of the difficulties encountered in developing animal models for the disease is that beta amyloid accumulation alone doesn’t lead to neurodegeneration, indicating that at least one other factor contributes to neuron death.
Recent research into the mystery has identified other players that may also contribute to neuron death in a so-called “double-hit” hypothesis. An important area of inquiry involves vascular function and how impairments in the body’s ability to maintain the vital blood-brain barrier and support blood vessel repair and growth within the brain may contribute to AD. Multiple lines of evidence have implicated neurovascular dysfunction in the disease mechanism, including genes implicated in genome-wide association studies. One gene, MEOX2, is important for vascular development and differentiation and is associated with early, severe AD in human patients. Nonetheless, the actual role MEOX2 plays in AD had not been studied.
In a paper recently published in Neurobiology of Aging, a team led by JAX Assistant Professor Gareth Howell, Ph.D., used a mouse model for AD, B6.APP/PS1 (B6.APBTg), to investigate the consequences of insufficient Meox2 expression. The mice typically accumulate beta-amyloid plaques but exhibit no neurodegeneration. When made haploinsufficent, however, meaning that the mice had only one functional copy of the gene instead of the normal two, the mice showed increased neuronal loss, particularly in areas containing beta-amyloid plaques. They also displayed cognitive decline, the most significant disease trait for human patients.