Amyloid beta emerges from below the neck to disable the brain

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.

Funding: TET received funding from the National Institutes of Health (K01 AG057862) and GK received funding from the Alzheimer's Association (AARFD-19-616386). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests:
The authors have declared that no competing interests exist.
APP carrying the familial Alzheimer disease Swedish (KM670/671NL) and Indiana (V717F) mutations and bred it with a previously established liver cell-specific Alb-Cre mouse line [7] to make hepatocyte-specific human amyloid (HSHA) mice. An important consideration when using a cell-specific Cre mouse line such as this is that unexpected transient expression of Cre recombinase may occur in other cell types or tissues. Importantly, the authors confirmed specificity by detection of high levels of mRNA for the human APP transgene in the liver of HSHA mice, with no significant detection of mRNA for the transgene in the brain, duodenum, or lung. Despite the apparent lack of APP transgene expression in the brain during aging, positron emission tomography (PET) imaging in vivo showed that the HSHA mice had an agedependent increase in Aβ deposition in the brain. This suggests that human Aβ produced in the liver can enter the brain. Notably, more than a decade ago, researchers showed that Aβ administration into the periphery by intraperitoneal injection causes β-amyloidosis in the brain [8], yet how Aβ is transported across the blood-brain barrier and whether it involves the association of Aβ with lipoproteins or a breakdown of the blood-brain barrier remain unclear.
Commonly used transgenic mouse models with human APP transgenes carrying familial mutations that produce high Aβ levels in the central nervous system recapitulate important features of Alzheimer disease. Studies on these mice have long served as a foundation for the advancement of new therapies. The age-dependent pathological phenotypes reported in the HSHA mice created by Lam and colleagues include abnormal lipid accumulation in the brain, neurodegeneration, and the dysfunction of capillaries associated with lipofuscin aggregation. The HSHA mice also demonstrated impaired performance in the passive avoidance test of hippocampal-dependent memory at 12 months of age. Other human APP mouse models with Aβ produced in the brain can have more aggressive Alzheimer disease-related pathology and earlier onset cognitive impairments in a range of behavioral tests. It is important to consider that the extent of the pathological effect of peripheral Aβ on the brain may depend on a limited Aβ produced in the liver contributes to disease-related pathology in the brain. Lam and colleagues generated HSHA transgenic mice that produce pathogenic Aβ specifically in the liver. Liver-derived Aβ travels through the circulatory system and crosses the blood-brain barrier to enter the brain. Aβ accumulation in the brain drives Alzheimer disease-related pathology including capillary dysfunction, inflammation, and neurodegeneration. Created with BioRender.com. AAU : Anabbreviationlisthasbeencompiled β, amyloid beta; HSHA, hepatocyte-specific human amyloid.
https://doi.org/10.1371/journal.pbio.3001388.g001 amount of Aβ that enters the brain and the region where it accumulates upon entry. Nevertheless, this new study supports that peripheral Aβ is sufficient to promote pathological diseaseassociated features in the brain and memory impairment.
Could targeting peripheral Aβ be another strategy to prevent neurodegeneration? Pharmacological reduction of Aβ levels in the blood of wild-type mice by peripheral administration of a drug impermeable to the blood-brain barrier was linked to reduced Aβ levels in the brain [9]. Dietary fatty acids can also modulate plasma Aβ levels in wild-type mice [10]. These findings provide evidence that Aβ levels in blood can be modulated; however, further studies are needed to establish whether or not peripherally targeted strategies to reduce Aβ would be beneficial for brain function and cognition in the context of Alzheimer disease. Historically, many different approaches have been explored to try to reduce Aβ levels in the brain as a diseasemodifying therapy for Alzheimer disease [11]. However, numerous clinical trials on therapies targeting Aβ have failed and did not meet expectations to slow cognitive decline in patients with symptomatic Alzheimer disease. This obstacle to finding an effective disease-modifying treatment for Alzheimer disease could be attributed to the complexity of the mechanisms that contribute to the disease progression that involves multiple pathologies [12]. Thus, lowering Aβ levels in combination with targeting other pathogenic factors in Alzheimer disease may be necessary to ameliorate cognitive decline. It is also possible that therapies directed against peripheral Aβ in addition to Aβ produced in the brain could serve to further dampen amyloid toxicity in the brain. The HSHA transgenic mice created and characterized by Lam and colleagues in this report could be used to further interrogate the therapeutic potential of targeting peripheral Aβ production to reduce the risk of Alzheimer disease.