Progressive Spread of Beta-amyloid Pathology in an Olfactory-driven Amyloid Precursor Protein Mouse Model

before Alzheimer's disease (AD) is diagnosed, patients experience an impaired sense of smell, and p-amyloid plaques accumulate within the olfactory mucosa and olfactory bulb (OB). The olfactory vector hypothesis proposes that external agents cause p-amyloid to aggregate and spread from the OB to connected downstream brain regions. To reproduce the slow accumulation of p-amyloid that occurs in human AD, we inves-tigated the progressive accumulation of p-amyloid across the brain using a conditional mouse model that over-expresses a humanized mutant form of the amyloid precursor protein (hAPP) in olfactory sensory neurons. Using design-based stereology, we show the progressive accumulation of p-amyloid plaques within the OB and cortical olfactory regions with age. We also observe reduced OB volumes in these mice when hAPP expres-sion begins prior-to but not post-weaning which we tracked using manganese-enhanced MRI. We therefore con-clude that the reduced OB volume does not represent progressive degeneration but rather disrupted OB development. Overall, our data demonstrate that hAPP expression in the olfactory epithelium can lead to the accumulation and spread of p-amyloid through the olfactory system into the hippocampus, consistent with an olfactory system role in the early stages of p-amyloid-related AD progression.Published by Elsevier Ltd on behalf of IBRO.