Neuron-Driven Vascular Degeneration in Familial Alzheimer’s Disease
Gama Sosa MA, Gasperi RD, Rocher AB, Wang AC, Janssen WG, Flores T, Perez GM, Schmeidler J, Dickstein DL, Hof PR, Elder GA. Age-related vascular pathology in transgenic mice expressing presenilin 1-associated familial Alzheimer’s disease mutations. Am J Pathol 2010;176(1):353-368. doi: 10.2353/ajpath.2010.090482.
Background: Familial Alzheimer’s disease (FAD) is associated with presenilin 1 (PS1) mutations that may affect neuronal and vascular integrity. Vascular pathology, including basement membrane alterations and capillary degeneration, is a frequent but poorly understood feature of Alzheimer’s disease. This study examined whether PS1 mutations alone are sufficient to induce vascular abnormalities in the absence of amyloid plaque deposition.
Hypothesis: This study hypothesized that expression of PS1 FAD mutations in neurons disrupts vascular structure and integrity, producing age-related microvascular pathology similar to that seen in Alzheimer’s disease.
Methods: The authors used transgenic mice expressing either wild-type or FAD-mutant human PS1 (M146V and P117L). Brain vasculature was analyzed in 50-µm coronal sections immunostained for collagen IV. Stereologic quantification of hippocampal vasculature was performed using a Zeiss Axioplan 2 microscope and Stereo Investigator with the Space Balls probe. Electron microscopy was used to assess ultrastructural changes.
Results: PS1 FAD-mutant mice exhibited age-dependent vascular attrition, decreased hippocampal capillary length density and thickened, dystrophic basement membranes. Electron microscopy revealed degenerated endothelial cells, irregular lumens and string vessel formation, despite intact surrounding neuropil. No congophilic amyloid was detected.
Conclusions: Neuronal expression of PS1 FAD mutations alone induces microvascular pathology, suggesting that mutant PS1 disrupts neuron–vascular signaling and contributes to Alzheimer’s disease–related vascular degeneration independent of amyloid deposition.
