. Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science. 2010 Nov 12;330(6006):980-2. PubMed.


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  1. McGowan et al. showed in 2005 that Aβ1-42 is essential for amyloid deposition in the parenchyma and also in vessels. The Aβ42 mice, but not the Aβ40 Tg, developed CAA and compact amyloid plaques. Mice crossed with Aβ42 and mutant APP (Tg2576) mice also developed a massive increase in amyloid deposition, suggesting that Aβ42 is essential for amyloid deposition in the parenchyma and also in vessels.

    View all comments by luisa Onstead
  2. This is extremely interesting and suggests that adoption of an early prophylactic treatment for reduction of Aβ in the blood/tissues by singular or composite (safe) mechanisms over the long term may reduce the likelihood of brain amyloidosis in the aging population. In this respect, the combinatorial complexity of enzymes and bioactive compounds or dietary factors over long periods could play a very important role.

    My own interest and casual research focuses on low levels of copper and/or high levels of zinc in the classic Western diet, which, coupled with low intake of spices as bioactive compounds, may be long-term contributory factors to dementia. Greater statistical dietary data would be helpful to assess this area more fully.

    I am rather concerned that many homeopaths, who routinely seem to detect “high” levels of copper in hair samples (and without blood analysis), provide treatments with zinc (which is a copper antagonist) when it is not clear to many such practitioners that there are a large number of enzymes that compete for copper reserves in the human body. Hair sample data by itself are not likely to be indicative of the overall enzyme distribution because copper-based enzymes that are in sufficient numbers only when copper intake is high could influence Aβ levels in the blood and body tissues over the long term.

  3. Prion-like behavior of amyloid-β or corticosterone-induced cerebral β-amyloidosis?

    Eisele and colleagues (1) reported increased cerebral amyloidosis in amyloid precursor protein (APP) transgenic (tg) mice after intraperitoneal inoculation with β-amyloid-rich brain extract from aged APP23 tg mice. In contrast, intraperitoneal inoculation with phosphate-buffered saline or brain extract from age-matched, non-tg wild-type mice had no effect on cerebral amyloidosis.

    The induction of brain plaques only through peripheral injection of Aβ-containing brain extracts led the authors to consider that a prion-like mechanism might have contributed to these brain lesions.

    However, neither these authors nor the accompanying Perspective (2) considered a more obvious and parsimonious explanation for this observation.

    Activation of the hypothalamo-pituitary-adrenal (HPA) axis leading to increased circulating plasma corticosterone, which crosses the blood-brain barrier, can emerge in response to immune challenges (3). Elevations in corticosterone levels have also have been consistently associated with increased brain amyloid-β levels and amyloid plaque deposition (4-6).

    Thus, without a consideration of potential differential effects of the three immune challenges on HPA axis activation, arguments ascribing these brain lesions and the pathogenesis of AD to prion-like behavior of amyloid-β are premature and not persuasive.


    . Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis. Science. 2010 Nov 12;330(6006):980-2. PubMed.

    . Medicine. Prion-like behavior of amyloid-beta. Science. 2010 Nov 12;330(6006):918-9. PubMed.

    . Interactions between the immune and neuroendocrine systems. Prog Brain Res. 2010;181:43-53. PubMed.

    . Corticosterone and related receptor expression are associated with increased beta-amyloid plaques in isolated Tg2576 mice. Neuroscience. 2008 Jul 31;155(1):154-63. PubMed.

    . Behavioral stress accelerates plaque pathogenesis in the brain of Tg2576 mice via generation of metabolic oxidative stress. J Neurochem. 2009 Jan;108(1):165-75. PubMed.

    . Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer's disease. J Neurosci. 2006 Aug 30;26(35):9047-56. PubMed.

  4. Is this effect related to antibodies to β amyloid generated by inoculation? Such effects may be relevant to the proposed use of β amyloid antibodies in Alzheimer's disease, and to their toxicity (Ferrer et al., 2004). Immunization with tau in mice also produces neurofibrillary tangles, axonal damage, and gliosis, illustrating the dangers of generating antibodies to self (Rosenmann et al., 2006).


    . Tauopathy-like abnormalities and neurologic deficits in mice immunized with neuronal tau protein. Arch Neurol. 2006 Oct;63(10):1459-67. PubMed.

    . Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease. Brain Pathol. 2004 Jan;14(1):11-20. PubMed.

  5. Eisele et al. reported that intravenous, intraocular, intranasal, and oral inoculations yielded no detectable induction of cerebral β amyloidosis in APP23 transgenic mice after four and eight months (1). Only intraperitoneal injections appear to induce this effect on the brain. This is baffling to me. If the spread of amyloidosis is through blood transmission, why did intravenous injections from the previous paper not show the same result? Why did only intraperitoneal inoculations have this effect? Amyloid spread through the peritoneal cavity seems highly unlikely under natural circumstances.

    The peritoneal cavity in humans is anatomically closed in males. In females, only the Fallopian tubes are exposed to the peritoneal cavity. It seems highly unlikely that Alzheimer's disease progression is exacerbated or caused through this fashion.

    I also find it highly perturbing to find multiple online reports suggesting that amyloidosis can be transmitted through a prion-like fashion, or that it can be spread intramuscularly or intravenously. This is directly contradicted by the data in the previous paper by Eisele et al.


    . Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12926-31. PubMed.

  6. Reply to comments by Christopher Carter, Nunzio Pomara, and Gabrielle Lake
    We thank Drs. Carter, Pomara, and Lake for their thoughtful comments on our work.

    Christopher Carter asks whether our observations may be related to antibodies to β amyloid generated by the inoculation. We have considered the possibility that exposure to exogenous Aβ could generate anti-β amyloid antibodies in the seeded mice. As noted in this study (Eisele et al., 2010) and in a previous study (Meyer-Luehmann et al., 2006), we did not find detectable Aβ-antibody titers in response to the inoculation.

    Nunzio Pomara suggests that elevated corticosteroid levels could explain our observation of cerebral β amyloid induction after intraperitoneal application of β amyloid-containing extracts. Dozens of studies are published per year describing various mechanisms that augment cerebral Aβ aggregation/deposition, as well as potential strategies designed to modulate cerebral β amyloidosis in APP-transgenic mice (see, e.g., Zahs and Ashe, 2010; Jucker, 2010). There is no question that APP expression, as well as the generation and aggregation of Aβ, can be influenced by a variety of factors, corticosteroids among them. However, for several reasons, we believe that the most parsimonious explanation for our findings is the induction of cerebral β amyloid by Aβ seeds traveling from the peritoneal cavity:

    First, no β amyloid induction occurred after the intraperitoneal application of wild-type brain extract or by brain extracts from young, pre-depositing APP-transgenic mice (unpublished observations). If the corticosteroid idea is true, one would have to assume that the misfolded Aβ (or a substance that is associated with misfolded Aβ) in the brain extract specifically activates the hypothalamo-pituitary-adrenal (HPA) axis. While this is theoretically possible, the absence of obvious differences in inflammation between groups (see below) suggests that it is an unlikely explanation of our observations.

    Second, we found no evidence of chronic inflammation and no difference between wild-type brain extract and β amyloid-containing transgenic brain extract in inducing systemic or even CNS-specific acute inflammation.

    Third, corticosteroids have been described to affect APP levels and Aβ generation in brain, and not specifically in the vasculature (e.g., Green et al., 2006). With this in mind, it would be difficult to explain the predominant induction of β amyloid in the vasculature first, followed by spreading into the parenchyma.

    Fourth, it is unclear how a corticosteroid mechanism could explain why it takes six to seven months (in the absence of inflammation) for the induction of β amyloid, and why, in our most recent studies (unpublished), this incubation time appears to be mouse strain dependent.

    Fifth, we have shown that intracerebral injections of β amyloid-containing brain extracts initiate Aβ deposition through a “prion-like” templated conversion. This is most convincingly demonstrated by the observation that the induced amyloid phenotype is dependent on the Aβ-type in the extract (Meyer-Luehmann et al., 2006). For these reasons, we feel that a prion-like mechanism is the most likely explanation for our observations.

    Gabriel Lake asks why intravenous injections in our previous paper (Eisele et al., 2009) did not induce β amyloid induction in the brain. A simple explanation may be that, in the previous study, the examined post-inoculation time was not long enough, or the amount of extract used was not high enough (for the intravenous inoculation we used 5 percent of the amount used for the intraperitoneal inoculation). In the transmission of prion disease, different routes of exposure have widely different efficacies. Additional experiments are needed to address this issue with regard to the induction of cerebral Aβ deposition.


    . Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science. 2006 Sep 22;313(5794):1781-4. PubMed.

    . 'Too much good news' - are Alzheimer mouse models trying to tell us how to prevent, not cure, Alzheimer's disease?. Trends Neurosci. 2010 Aug;33(8):381-9. PubMed.

    . The benefits and limitations of animal models for translational research in neurodegenerative diseases. Nat Med. 2010 Nov;16(11):1210-4. PubMed.

    . Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer's disease. J Neurosci. 2006 Aug 30;26(35):9047-56. PubMed.

    . Induction of cerebral beta-amyloidosis: intracerebral versus systemic Abeta inoculation. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12926-31. PubMed.

  7. See also Sutcliffe et al., 2011.


    . Peripheral reduction of β-amyloid is sufficient to reduce brain β-amyloid: implications for Alzheimer's disease. J Neurosci Res. 2011 Jun;89(6):808-14. PubMed.

    View all comments by Steve Barger

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