Aggregated forms of Aβ not only spread within the brain, they also travel from peripheral tissues to the brain to seed amyloid pathology there, at least in mice. Mathias Jucker and colleagues at the Hertie Institute for Clinical Brain Research in Tübingen, Germany, first described this phenomenon in 2010. The finding tightened the analogy between Alzheimer’s and prion disease, which also passes from periphery to brain. Now, in the July 30 Journal of Neuroscience, Jucker and colleagues report that unlike prions, Aβ aggregates can directly infiltrate the brain without needing to first replicate in the body. It remains unclear exactly how the peptide gets in; however, the data hint that it may hitch a ride inside blood monocytes. “The results imply that some [amyloid] seeds may have a peripheral origin,” Jucker wrote to Alzforum. Whether this occurs in human Alzheimer’s disease, however, is still unknown.

Other researchers found the paper intriguing. “The authors obtained similar results in several different transgenic mouse lines, which underlines the robustness of this seeding paradigm,” said Jan Stöhr, who works with Stanley Prusiner at the University of California, San Francisco. “It parallels our experience with PrP prions.”

Jucker’s initial studies involved brain extract from aged AD mice injected into the peritoneal cavity, or abdominal space, of young transgenic APP23 mice, which express human APP with the Swedish mutation in brain. The inoculation kicked off brain amyloid deposition (see Oct 2010 news story). But how did aggregates trigger amyloidosis? Because these mice expressed murine APP in body tissues, the researchers considered the possibility that misfolded Aβ first multiplied in the periphery, as prions do.

Aβ aggregates (dark blue dots) inside monocytes (purple cells) one day after injection of brain extract from aged AD mice. [Image courtesy of Eisele et al., The Journal of Neuroscience, 2014.]

To investigate this, joint first authors Yvonne Eisele, Sarah Fritschi, and Tsuyoshi Hamaguchi repeated the experiments in APP23 mice as well as in two additional models: APP23 mice that lacked endogenous APP and thus had no peripheral Aβ, and R1.40 mice, which overexpress human mutant APP throughout peripheral organs and tissues as well as brain. All three models developed brain amyloid plaques within six to eight months after intraperitoneal injection. At that age, the brains of their littermates injected intraperitoneally with wild-type brain extract remained pristine.

The amount of amyloidosis correlated with levels of APP in brain, but not peripheral tissues, the authors found. APP23 mice, which express two to three times as much transgenic APP as do R1.40 mice, had two to three times more brain Aβ. They developed plaques two months earlier than did the R1.40s. Mice with the APP23 strain that lacked peripheral APP grew brain plaques just as quickly as their counterparts. Peripheral Aβ did not seem to matter.

The amount of seed did matter, however. Injected extracts had to contain a minimum of 400 ng of Aβ to seed brain amyloidosis, rendering this peripheral inoculation route 1000-fold less potent than direct injection into the brain, the authors noted. Mixing the extract with an anti-Aβ antibody before injection prevented seeding, further showing that it was Aβ in the extract that spurred amyloid deposition.

The data implied that injected Aβ directly enters brain. But how? The authors saw that amyloid deposits clustered around blood vessels in several brain areas, including the frontal, entorhinal, and parietal cortex, as well as the hippocampus. The pattern suggested entry through the bloodstream.

One day after injection, peripheral blood monocytes contained numerous Aβ aggregates (see image above); the quantity dropped off sharply after one week, and was undetectable by one month. Monocytes have been shown to transfer Aβ seeds to peripheral tissues (see Sponarova et al., 2008). These cells also slip into the brain when needed, raising the possibility that they could provide the means of entry for Aβ.

It is also possible that multimeric Aβ passes directly from the bloodstream to the brain, perhaps by receptor-mediated or passive transport, noted Claudio Soto at the University of Texas Medical School in Houston. For example, the receptor for advanced glycation end products (RAGE) has been shown to transport Aβ across the blood-brain barrier (see Deane et al., 2003). Meanwhile, Stöhr speculated that injected Aβ might be taken up by peripheral nerve endings. Jucker agreed these are possibilities, noting, “Our data do not rule out the possible existence of multiple pathways by which Aβ seeds can enter the brain.” To trace the path of entry, researchers could inject radiolabeled Aβ and follow its fate, Soto suggested.

Why does this matter to humans? Could aggregated Aβ from one person enter another’s person’s body through a blood transfusion or on a surgical instrument, and cause Alzheimer’s disease? Two small epidemiological studies have found no correlation between blood transfusions and AD risk (see Bohnen et al., 1994; O’Meara et al., 1997), but Soto suggested it might be worth looking at larger datasets. Researchers noted, however, that the present experiments were done in mice that overexpress mutant APP, and hence might not translate to people.

Intriguingly, peripheral injection of aggregated tau stimulates tauopathy in tau-transgenic mice (see Clavaguera et al., 2014), hinting that brain uptake of protein aggregates might be a common phenomenon, Jucker said. He thinks peripheral aggregates might have diagnostic potential. “A key question for future research is whether Aβ seeds are present in bioactive form and quantity in the blood, particularly in humans. A variety of novel and sensitive ELISAs are in development that should be able to address this question,” he wrote.—Madolyn Bowman Rogers


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Research Models Citations

  1. APP23
  2. APP(Swedish) (R1.40)

News Citations

  1. Peripheral Aβ Seeds CAA and Parenchymal Amyloidosis

Paper Citations

  1. . AA-amyloidosis can be transferred by peripheral blood monocytes. PLoS One. 2008 Oct 2;3(10):e3308. PubMed.
  2. . RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med. 2003 Jul;9(7):907-13. PubMed.
  3. . Prior blood transfusions and Alzheimer's disease. Neurology. 1994 Jun;44(6):1159-60. PubMed.
  4. . Alzheimer's disease and history of blood transfusion by apolipoprotein-E genotype. Neuroepidemiology. 1997;16(2):86-93. PubMed.
  5. . Peripheral administration of tau aggregates triggers intracerebral tauopathy in transgenic mice. Acta Neuropathol. 2014 Feb;127(2):299-301. Epub 2013 Dec 21 PubMed.

Further Reading

Primary Papers

  1. . Multiple factors contribute to the peripheral induction of cerebral β-amyloidosis. J Neurosci. 2014 Jul 30;34(31):10264-73. PubMed.