Amyloid Plaques Do Not Predict Neuronal Loss in an Alzheimer’s Disease Model

Schmitz C, Rutten BP, Pielen A, Schäfer S, Wirths O, Tremp G, Czech C, Blanchard V, Multhaup G, Rezaie P, Korr H, Steinbusch HW, Pradier L, Bayer TA. Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer’s disease. Am J Pathol 2004;164(4):1495-1502. doi: 10.1016/S0002-9440(10)63235-X.

Background: Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) accumulation, neurofibrillary tangles and neuronal loss. While transgenic mouse models expressing mutant human amyloid precursor protein (APP) or presenilin-1 (PS-1) develop Aβ plaques, the relationship between plaque formation and neuronal degeneration has remained unclear.

Hypothesis: This study hypothesized that neuronal loss in AD could occur independently of amyloid plaque load and that mechanisms beyond Aβ aggregation contribute to neurodegeneration.

Methods: The authors examined hippocampal neurons in transgenic mice expressing human mutant APP751 and PS-1 (M146L). Using unbiased stereologic quantification with the Optical Fractionator implemented in Stereo Investigator, together with image analyses and immunohistochemistry for Aβ, GFAP and NeuN, they quantified hippocampal neuron numbers and plaque load. Additional imaging was performed with digital photomicroscopy and Imaris-based analysis.

Results: APP/PS-1 double-transgenic mice showed a significant, age-related (~35%) loss of hippocampal pyramidal neurons, whereas PS-1-only and control mice did not. Neuron loss exceeded local plaque accumulation, showed no correlation with Aβ load, and was also observed in regions distant from plaques. Granule cells of the dentate gyrus were unaffected.

Conclusions: The findings indicate that hippocampal neuron loss in APP/PS-1 mice surpasses amyloid plaque burden, suggesting that multiple mechanisms, including non-plaque-related Aβ toxicity, contribute to neurodegeneration in AD.