Year: 2021
Type: article
Abstract: Accumulation of amyloid beta (Aβ) in the brain in Alzheimer disease drives pathophysiology. A study in this issue of PLOS Biology revealed that Aβ from the liver can promote brain pathology, supporting that peripheral Aβ can contribute to neurodegeneration.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].Higher levels of Aβ peptide isoforms were found in the blood of individuals with pathological Aβ accumulation in brain and cognitive impairment [2].This correlative increase in Aβ could be due to the transfer of brain-derived Aβ across the blood-brain barrier as a mechanism of Aβ clearance.On the other hand, Aβ found in blood is associated with lipoprotein particles, and various reports provide evidence that peripheral lipogenic organs could be another source of Aβ peptides in the blood [5,6].However, given the robust accumulation and effect of Aβ originating in the central nervous system, the potential impact of peripheral Aβ on the brain in disease etiology is often overlooked.Lam and colleagues sought to AU : Anabbreviationlisthasb address this gap in knowledge in the neurodegeneration field by elucidating the effect of peripheral Aβ on the brain.They created a knock-in mouse for Cre recombinase-dependent expression of human
Source: PLoS Biology
Authors: Grant Kauwe, Tara E. Tracy
Institution: Buck Institute for Research on Aging
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,000
OpenAlex ID: W3201351720