Alzheimer disease is the most common type of dementia, and it is characterized by the presence of amyloid plaques in the brain that are comprised of aggregated amyloid beta (Aβ) peptides. The Aβ peptide is a fragment of the larger integral membrane protein called amyloid precursor protein (APP) that is expressed in neurons of the brain. When APP is cleaved by β and ɣ secretase enzymes, the resulting Aβ peptides form small soluble aggregates that induce toxicity in the brain and neuronal dysfunction followed by the deposition of Aβ peptides into insoluble amyloid plaques. Many studies have demonstrated that transgenic mice with expression of human APP carrying Alzheimer disease–causing mutations in the brain have high levels of toxic Aβ, neuronal pathophysiology, memory impairments, and plaque formation [1]. The deleterious impact of Aβ produced inside the brain related to memory loss and Alzheimer disease is clear, but Aβ can also be detected outside of the central nervous system in the blood where it has growing potential as an effective biomarker for Alzheimer disease [2]. The soluble Aβ detected in blood could be peptides that are cleared into the blood from the brain [3], but Aβ can also originate from cells in the periphery. Whether peripheral production of Aβ can contribute to Alzheimer disease pathogenesis is not clear. Now, Lam and colleagues have generated a new transgenic mouse with expression of human mutant APP primarily in the liver to investigate whether peripheral production of Aβ is sufficient to promote neurodegenerative phenotypes in the brain (Fig 1) [4].

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