----- Original Message -----
From: Senator Kay Bailey Hutchison
To: flounder9@verizon.net
Sent: Monday, October 25, 2010 11:32 AM
Subject: Constituent Response From Senator Kay Bailey Hutchison
Dear Friend:
Thank you for contacting me regarding funding for Alzheimer’s disease. I welcome your thoughts and comments.
On July 22, 2009, Senator Barbara Mikulski (D-MD) introduced S. 1492, the Alzheimer’s Breakthrough Act. This bill would increase Alzheimer’s research funding through the National Institutes of Health (NIH) from $400 million to $2 billion in 2010. The legislation would also establish a National Summit on Alzheimer’s disease to coordinate researchers, policymakers and public health professionals. Additionally, it would expand the Alzheimer’s State Matching Grant Program as well as the Alzheimer’s 24/7 call center to provide updated resources and tools for caregivers, family members and those affected in a multilingual capacity.
The Alzheimer’s Breakthrough Act has been referred to the Senate Committee on Health, Education, Labor and Pensions, on which I do not serve. Should this legislation come before the full Senate for a vote, you may be certain I will keep your views in mind.
I am a strong proponent of biomedical research to help discover the causes of and cures for diseases like Alzheimer’s. I recently supported an amendment introduced by Senator Tom Harkin (D-IA) to H.R. 1, America’s Recovery and Reinvestment Act, which appropriated $6.5 billion to the NIH.
As a member of the Senate Appropriations Committee, I worked to include more than $945 million for chronic disease prevention, health promotion and genomics in the FY 2010 Labor, Health and Human Services, Education, and Related Agencies Appropriations Bill (H.R. 3293). This funding is almost a $65 million increase from FY 2009 and includes $2 million specifically for Alzheimer's disease. I also worked with the Committee to include approximately $1.1 billion for the National Institute on Aging (NIA) and strongly urged the NIA to devote more funding to clinical studies and the renewal of the Alzheimer's Disease Neuroimaging Initiative. H.R. 3293 was passed by the Senate Appropriations Committee on July 30, 2009, and is now ready to be considered by the full Senate.
I appreciate hearing from you, and I hope that you will not hesitate to contact me on any issue that is important to you.
Sincerely,
Kay Bailey Hutchison
United States Senator
284 Russell Senate Office Building
Washington, DC 20510
202-224-5922 (tel)
202-224-0776 (fax)
http://hutchison.senate.gov
PLEASE DO NOT REPLY to this message as this mailbox is only for the delivery of outbound messages, and is not monitored for replies. Due to the volume of mail Senator Hutchison receives, she requests that all email messages be sent through the contact form found on her website at http://hutchison.senate.gov/contact.cfm .
If you would like more information about issues pending before the Senate, please visit the Senator's website at http://hutchison.senate.gov . You will find articles, floor statements, and press releases, along with her weekly column and monthly television show on current events. You can also sign up to receive Senator Hutchison's weekly e-newsletter.
Thank you.
end
========================
BSE101/1 0136
IN CONFIDENCE
CMO
From: Dr J S Metters DCMO
4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
http://collections.europarchive.org/tna/20081106170650/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf
CJD1/9 0185
Ref: 1M51A
IN STRICT CONFIDENCE
From: Dr. A Wight
Date: 5 January 1993
Copies:
Dr Metters
Dr Skinner
Dr Pickles
Dr Morris
Mr Murray
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
Friday, September 3, 2010
Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE
http://betaamyloidcjd.blogspot.com/2010/09/alzheimers-autism-amyotrophic-lateral.html
http://betaamyloidcjd.blogspot.com/
2010 PRION UPDATE
Thursday, August 12, 2010
Seven main threats for the future linked to prions
http://prionpathy.blogspot.com/2010/08/seven-main-threats-for-future-linked-to.html
http://prionpathy.blogspot.com/
TSS
Friday, October 22, 2010
Peripherally Applied Aß-Containing Inoculates Induce Cerebral ß-Amyloidosis
http://betaamyloidcjd.blogspot.com/2010/10/peripherally-applied-containing.html
Thursday, October 28, 2010
Friday, October 22, 2010
Peripherally Applied Aß-Containing Inoculates Induce Cerebral ß-Amyloidosis
Peripherally Applied Aß-Containing Inoculates Induce Cerebral ß-Amyloidosis
Yvonne S. Eisele,1,2 Ulrike Obermüller,1,2 Götz Heilbronner,1,2,3 Frank Baumann,1,2 Stephan A. Kaeser,1,2
Hartwig Wolburg,4 Lary C. Walker,5 Matthias Staufenbiel,6 Mathias Heikenwalder,7 Mathias Jucker1,2*
1Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen,
Germany. 2DZNE - German Center for Neurodegenerative Diseases, Tübingen, Germany. 3Graduate School for Cellular and
Molecular Neuroscience, University of Tübingen, Tübingen, Germany. 4Department of Pathology, University of Tübingen,
Tübingen, Germany. 5Yerkes National Primate Research Center and Department of Neurology, Emory University, Atlanta, GA,
USA. 6Novartis Institutes for Biomedical Research, Neuroscience Discovery, Basel, Switzerland. 7Department of Pathology,
Institute for Neuropathology, University Hospital, Zürich, Switzerland.
*To whom correspondence should be addressed. E-mail: mathias.jucker@uni-tuebingen.de
The intracerebral injection of â-amyloid–containing brain extracts can induce cerebral â-amyloidosis and associated pathologies in susceptible hosts. Here, we found that intraperitoneal inoculation with â-amyloid–rich extracts induced â-amyloidosis in the brains of â-amyloid precursor protein transgenic mice after prolonged incubation times.
Intracerebral (i.c.) inoculation with minute amounts of brain extract containing misfolded ß-amyloid (Aß) from patients with Alzheimer’s Disease or from amyloid-bearing ß-amyloid precursor protein (APP) transgenic (tg) mice induces cerebral ß-amyloidosis and related pathologies in APP tg mice in a time- and concentration-dependent manner (1). However, oral, intravenous, intraocular, or intranasal inoculations have failed to induce cerebral ß-amyloidosis in APP tg hosts (2). These findings suggest that Aß-containing brain material in direct contact with the brain can induce cerebral ß-amyloidosis, but that, unlike prions, either the inducing agent is not readily conveyed from peripheral sites to the brain, or a higher concentration or longer incubation period is required for peripherally delivered Aß seeds.
Intraperitoneal (i.p.) administration of prion-rich material is more efficient at transmitting prion disease than is oral administration (3, 4). To test whether i.p. inoculation of Aß- rich material might similarly trigger Aß misfolding and deposition in the brain, we administered two i.p. injections (100 µl each, 1 week apart) of Aß-laden (10-20 ng/µl) brain extract from aged APP23 tg mice (Tg extract) to a cohort of young (2-month-old) female APP23 tg mice (5). After a 7-month incubation period, cerebral ß-amyloidosis was robustly induced in all i.p. inoculated mice compared to untreated littermate controls (Fig. 1). To confirm this finding, we inoculated a second cohort of 2-month-old female APP23 mice with a different batch of Tg brain extract in another laboratory (cohort 2: Tübingen, vs. cohort 1: Basel). After 6–7 months, mice injected i.p. with the Tg extract exhibited robust cerebral ß-amyloidosis, whereas i.p. inoculation with phosphate-buffered saline (PBS) or brain extract from agematched, non-tg wildtype mice (Wt extract) was ineffective (Fig. 1).
Induced ß-amyloidosis was strongest in the anterior and entorhinal cortices with additional deposition in the hippocampus, resembling the regional development of endogenous ß-amyloidosis in aged APP23 mice (6). However, whereas normal aged APP23 mice manifest mostly parenchymal deposits, the induced ß-amyloid in i.p. seeded mice was predominantly associated with blood vessels (cerebral ß-amyloid angiopathy [Aß-CAA]), often with massive spreading into the neighboring brain parenchyma (Fig. 1). The presence of Aß was confirmed by immunoblotting, and amyloid fibrils were evident ultrastructurally; in addition, the induced ß-amyloidosis was linked to gliosis, hyperphosphorylated tau, and other associated pathologies (Fig. 2), reminiscent of the cerebral ß-amyloid deposition in aged APP23 mice (6, 7).
To compare the efficiency and time course of i.p. versus i.c. inoculation, 2-month-old female APP23 mice were inoculated either i.p. (2 x 100 µl) or i.c. (2.5 µl into the hippocampus) with Tg extract, and then analyzed 4 months later. No cerebral ß-amyloid induction was found in any of the 4 i.p. inoculated mice, while all 6 i.c. inoculated mice revealed ß-amyloid induction identical to that previously reported (1, 2). From this observation, together with previous time course and 1:20 dilution experiments for i.c. inoculations (1), we estimate that i.p. inoculations with 103-fold more Aß take 2–5 months longer to induce cerebral ß-amyloidosis than do i.c. inoculations.
The replication of peripherally applied prions and their translocation into the central nervous system depend on hematopoietic and stromal immune cells, in combination with sympathetic innervation of abdominal lymphoid organs (8). Both activation of the immune system and chronic inflammation promote prion replication (9, 10). To assess the immune response to Aß-rich brain extracts, additional APP23 mice were given single i.p. injections of 200 µl Tg or Wt extract and sacrificed 1 hour, 1 week, or 1 month postinjection (5). An acute immune activation to the injected brain material was indicated by transient increases in plasma chemokines and cytokines (IL6, IL10, TNF-a, MCP-1, MIP-1ß) in both Tg and Wt extract-inoculated mice after 1 hour, with IL-6 still mildly elevated in Tg extract-injected mice 1 week post-inoculation (fig. S1). However, no signs of chronic inflammation in various peripheral organs (e.g. liver,pancreas, kidney, lung) or serum anti-Aß antibody titers were found in any mice investigated at 1 or 7 months postseeding (5). Moreover, no ß-amyloid deposition was found in any of the peripheral tissues at any time point studied.
Thus, like prion disease, cerebral ß-amyloidosis can be seeded in the brain by homologous protein aggregates delivered into the peritoneal cavity, although the i.p. route required more time and was less efficient than was direct injection into the brain (1, 2). The amyloid-inducing factor in the Tg extract is probably a species of misfolded Aß that is generated in its most effective form or composition in vivo (1). Because the expression of tg (human) APP is restricted to the nervous system in APP23 mice (7), in this model it is likely that the seed carried to the brain was the injected material itself, rather than Aß aggregates that were first amplified in peripheral tissues.
There is now persuasive evidence that the aggregation of Aß is a key pathogenic feature of AD and Aß-CAA (11–14), although the majority of these cases are initiated by unknown causes. The possibility that mechanisms exist allowing for the transport of Aß aggregates (and possibly other seeds) from the periphery to the brain justifies further studies to better understand the cellular and molecular origin of these diseases and to clarify the basis of infectious vs. non-infectious proteopathies (15, 16).
References and Notes
References and Notes
1. M. Meyer-Lühmann et al., Science 131, 1781 (2006).
2. Y. S. Eisele et al., Proc Natl Acad Sci USA 106, 12926
(2009).
3. S.B. Prusiner, Prion Biology and Diseases (Cold Spring
Harbor Laboratory Press), 2nd Ed pp. 1050 (2004).
4. R.H. Kimberlin, C.A. Walker, J Comp Path 88, 39 (1978).
5. For methods, see Supporting Online Material.
6. C. Sturchler-Pierrat et al., Proc Natl Acad Sci USA 94,
13287 (1997).
7. M.E. Calhoun et al., Proc Natl Acad Sci USA 96, 14088
(1999).
8. A. Aguzzi, C. Sigurdson, M. Heikenwälder, Ann Rev
Pathol Mech Dis 3, 11 (2008).
9. M. Heikenwalder et al., Science 307, 1107 (2005).
10. J. Bremer et al., PloS One 4, e7160 (2009).
11. J. Hardy, D. J. Selkoe, Science 297, 353 (2002).
12. M. Sorandt, M. A. Mintun, D. Head, J. C. Morris, Arch
Neurol 66, 1476 (2009).
13. J. C. Morris et al., Arch Neurol 66, 1469 (2009).
14. S. X. Zhang-Nunes et al., Brain Pathology 16, 30 (2006).
15. L. C. Walker, H. LeVine, M. P. Mattson, M. Jucker,
Trends Neurosci 29, 438 (2006).
16. A. Aguzzi, L. Rajendran, Neuron 64, 783 (2009).
17. We thank M.-J. Runser, L. Jacobson (Basel), F. Langer, J.
Coomaraswamy, S. Grathwohl, N. Varvel, T. Hamaguchi,
C. Schäfer, A. Bosch, G. Frommer-Kästle, U. Scheurlen
(Tübingen) for experimental help and A. Aguzzi (Zürich)
for insightful comments. Supported by the Competence
Network on Degenerative Dementias (BMBF-01GI0705),
the BMBF in the frame of ERA-Net NEURON
(MIPROTRAN), the CIN (DFG), and NIH RR-00165.
Supporting Online Material
www.sciencemag.org/cgi/content/full/science.1194516/DC1
Materials and Methods
Fig. S1
References
1 July 2010; accepted 24 September 2010
Published online 21 October 2010; 10.1126/science.1194516
Fig. 1. Induced Aß deposition. (A and B) Aß-immunostained frontal cortex of Tg extract- (A) and Wt extract- (B) i.p. inoculated APP23 mice. (C and D) Most induced ß-amyloid was vascular (Aß-CAA), with Aß-immunoreactivity extending into the brain parenchyma (arrows). Amyloid-laden vessels were congophilic (red in D; birefringent under crosspolarized light, insert) and often were surrounded by diffuse, Congo red-negative Aß deposits (arrowheads). (E and F) Analysis of the entire neocortex for Aß-CAA frequency (indicated are all three [I-III] CAA severity grades [5]), and for total Aß load in Tg extract-inoculated mice compared to control (Ctr) mice. Cohort 1 consisted of 6 Tg extractinoculated mice vs. 7 untreated control mice. Aß-CAA: t(11) = 6.78 (all severity grades combined), ***P < 0.0001; Aß load: t(11) = 8.79, ***P < 0.0001. Cohort 2 consisted of 5 Tg extract-inoculated mice vs. 5 Wt extract-inoculated mice and 4 PBS-injected mice. These latter 2 (control) groups did not differ significantly, and were combined for analysis. Aß-CAA: t(12) = 7.79, ***P < 0.0001; Aß load t(12) = 2.71, *P < 0.05. The occasional parenchymal Aß-deposits in control mice are normal for 9-month-old APP23 mice. Indicated are means ±SEM. Scale bars: 200 µm (A,B); 50 µm (C,D).
Fig. 2. Induced Aß deposition was linked to multiple associated pathologies. (A) Ultrastructural analysis showed amyloid deposition within the vascular basal lamina (BL), with typical amyloid fibrils (arrowheads) extending into the brain parenchyma. Insets are low- and high-magnification views of the examined vessel (L = lumen) and the typical non-branching amyloid fibrils. (B to E) Vascular amyloid(stained by Congo Red in B and C) and parenchymal plaques were surrounded by hypertrophic, Iba1-positive microglia (B), GFAP-positive astrocytes (C), hyperphosphorylated taupositive neurites (D; asterisk indicates amyloid core), but a paucity of proximate neurons (cresyl-violet stain, E). (F and G) Vessels with CAA types II and III showed smooth muscle cell loss at the site of amyloid deposition (arrowheads; confocal image, maximum projection of 5 µm z-stack: red, Aß; green, smooth muscle actin). A normal vessel (G) has a complete ring of smooth muscle cells. (H) Immunoblotting of micropunches of Aß-immunoreactive material revealed the expected Aß band. Synthetic Aß40/42 is shown as control. Markers = 3 and 6 kD. Scale bars: 1 µm (A; insets 5 and 0.5 µm); 50 µm (B-E); 10 µm (F, G).
end...see ;
Peripherally Applied Aß-Containing Inoculates Induce Cerebral ß-Amyloidosis
http://www.sciencemag.org/cgi/content/abstract/science.1194516
BSE101/1 0136
IN CONFIDENCE
CMO
From: Dr J S Metters DCMO
4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
http://collections.europarchive.org/tna/20081106170650/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf
CJD1/9 0185
Ref: 1M51A
IN STRICT CONFIDENCE
From: Dr. A Wight
Date: 5 January 1993
Copies:
Dr Metters
Dr Skinner
Dr Pickles
Dr Morris
Mr Murray
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
Friday, September 3, 2010
Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE
http://betaamyloidcjd.blogspot.com/2010/09/alzheimers-autism-amyotrophic-lateral.html
http://betaamyloidcjd.blogspot.com/
2010 PRION UPDATE
Thursday, August 12, 2010
Seven main threats for the future linked to prions
http://prionpathy.blogspot.com/2010/08/seven-main-threats-for-future-linked-to.html
http://prionpathy.blogspot.com/
TSS
Yvonne S. Eisele,1,2 Ulrike Obermüller,1,2 Götz Heilbronner,1,2,3 Frank Baumann,1,2 Stephan A. Kaeser,1,2
Hartwig Wolburg,4 Lary C. Walker,5 Matthias Staufenbiel,6 Mathias Heikenwalder,7 Mathias Jucker1,2*
1Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, D-72076 Tübingen,
Germany. 2DZNE - German Center for Neurodegenerative Diseases, Tübingen, Germany. 3Graduate School for Cellular and
Molecular Neuroscience, University of Tübingen, Tübingen, Germany. 4Department of Pathology, University of Tübingen,
Tübingen, Germany. 5Yerkes National Primate Research Center and Department of Neurology, Emory University, Atlanta, GA,
USA. 6Novartis Institutes for Biomedical Research, Neuroscience Discovery, Basel, Switzerland. 7Department of Pathology,
Institute for Neuropathology, University Hospital, Zürich, Switzerland.
*To whom correspondence should be addressed. E-mail: mathias.jucker@uni-tuebingen.de
The intracerebral injection of â-amyloid–containing brain extracts can induce cerebral â-amyloidosis and associated pathologies in susceptible hosts. Here, we found that intraperitoneal inoculation with â-amyloid–rich extracts induced â-amyloidosis in the brains of â-amyloid precursor protein transgenic mice after prolonged incubation times.
Intracerebral (i.c.) inoculation with minute amounts of brain extract containing misfolded ß-amyloid (Aß) from patients with Alzheimer’s Disease or from amyloid-bearing ß-amyloid precursor protein (APP) transgenic (tg) mice induces cerebral ß-amyloidosis and related pathologies in APP tg mice in a time- and concentration-dependent manner (1). However, oral, intravenous, intraocular, or intranasal inoculations have failed to induce cerebral ß-amyloidosis in APP tg hosts (2). These findings suggest that Aß-containing brain material in direct contact with the brain can induce cerebral ß-amyloidosis, but that, unlike prions, either the inducing agent is not readily conveyed from peripheral sites to the brain, or a higher concentration or longer incubation period is required for peripherally delivered Aß seeds.
Intraperitoneal (i.p.) administration of prion-rich material is more efficient at transmitting prion disease than is oral administration (3, 4). To test whether i.p. inoculation of Aß- rich material might similarly trigger Aß misfolding and deposition in the brain, we administered two i.p. injections (100 µl each, 1 week apart) of Aß-laden (10-20 ng/µl) brain extract from aged APP23 tg mice (Tg extract) to a cohort of young (2-month-old) female APP23 tg mice (5). After a 7-month incubation period, cerebral ß-amyloidosis was robustly induced in all i.p. inoculated mice compared to untreated littermate controls (Fig. 1). To confirm this finding, we inoculated a second cohort of 2-month-old female APP23 mice with a different batch of Tg brain extract in another laboratory (cohort 2: Tübingen, vs. cohort 1: Basel). After 6–7 months, mice injected i.p. with the Tg extract exhibited robust cerebral ß-amyloidosis, whereas i.p. inoculation with phosphate-buffered saline (PBS) or brain extract from agematched, non-tg wildtype mice (Wt extract) was ineffective (Fig. 1).
Induced ß-amyloidosis was strongest in the anterior and entorhinal cortices with additional deposition in the hippocampus, resembling the regional development of endogenous ß-amyloidosis in aged APP23 mice (6). However, whereas normal aged APP23 mice manifest mostly parenchymal deposits, the induced ß-amyloid in i.p. seeded mice was predominantly associated with blood vessels (cerebral ß-amyloid angiopathy [Aß-CAA]), often with massive spreading into the neighboring brain parenchyma (Fig. 1). The presence of Aß was confirmed by immunoblotting, and amyloid fibrils were evident ultrastructurally; in addition, the induced ß-amyloidosis was linked to gliosis, hyperphosphorylated tau, and other associated pathologies (Fig. 2), reminiscent of the cerebral ß-amyloid deposition in aged APP23 mice (6, 7).
To compare the efficiency and time course of i.p. versus i.c. inoculation, 2-month-old female APP23 mice were inoculated either i.p. (2 x 100 µl) or i.c. (2.5 µl into the hippocampus) with Tg extract, and then analyzed 4 months later. No cerebral ß-amyloid induction was found in any of the 4 i.p. inoculated mice, while all 6 i.c. inoculated mice revealed ß-amyloid induction identical to that previously reported (1, 2). From this observation, together with previous time course and 1:20 dilution experiments for i.c. inoculations (1), we estimate that i.p. inoculations with 103-fold more Aß take 2–5 months longer to induce cerebral ß-amyloidosis than do i.c. inoculations.
The replication of peripherally applied prions and their translocation into the central nervous system depend on hematopoietic and stromal immune cells, in combination with sympathetic innervation of abdominal lymphoid organs (8). Both activation of the immune system and chronic inflammation promote prion replication (9, 10). To assess the immune response to Aß-rich brain extracts, additional APP23 mice were given single i.p. injections of 200 µl Tg or Wt extract and sacrificed 1 hour, 1 week, or 1 month postinjection (5). An acute immune activation to the injected brain material was indicated by transient increases in plasma chemokines and cytokines (IL6, IL10, TNF-a, MCP-1, MIP-1ß) in both Tg and Wt extract-inoculated mice after 1 hour, with IL-6 still mildly elevated in Tg extract-injected mice 1 week post-inoculation (fig. S1). However, no signs of chronic inflammation in various peripheral organs (e.g. liver,pancreas, kidney, lung) or serum anti-Aß antibody titers were found in any mice investigated at 1 or 7 months postseeding (5). Moreover, no ß-amyloid deposition was found in any of the peripheral tissues at any time point studied.
Thus, like prion disease, cerebral ß-amyloidosis can be seeded in the brain by homologous protein aggregates delivered into the peritoneal cavity, although the i.p. route required more time and was less efficient than was direct injection into the brain (1, 2). The amyloid-inducing factor in the Tg extract is probably a species of misfolded Aß that is generated in its most effective form or composition in vivo (1). Because the expression of tg (human) APP is restricted to the nervous system in APP23 mice (7), in this model it is likely that the seed carried to the brain was the injected material itself, rather than Aß aggregates that were first amplified in peripheral tissues.
There is now persuasive evidence that the aggregation of Aß is a key pathogenic feature of AD and Aß-CAA (11–14), although the majority of these cases are initiated by unknown causes. The possibility that mechanisms exist allowing for the transport of Aß aggregates (and possibly other seeds) from the periphery to the brain justifies further studies to better understand the cellular and molecular origin of these diseases and to clarify the basis of infectious vs. non-infectious proteopathies (15, 16).
References and Notes
References and Notes
1. M. Meyer-Lühmann et al., Science 131, 1781 (2006).
2. Y. S. Eisele et al., Proc Natl Acad Sci USA 106, 12926
(2009).
3. S.B. Prusiner, Prion Biology and Diseases (Cold Spring
Harbor Laboratory Press), 2nd Ed pp. 1050 (2004).
4. R.H. Kimberlin, C.A. Walker, J Comp Path 88, 39 (1978).
5. For methods, see Supporting Online Material.
6. C. Sturchler-Pierrat et al., Proc Natl Acad Sci USA 94,
13287 (1997).
7. M.E. Calhoun et al., Proc Natl Acad Sci USA 96, 14088
(1999).
8. A. Aguzzi, C. Sigurdson, M. Heikenwälder, Ann Rev
Pathol Mech Dis 3, 11 (2008).
9. M. Heikenwalder et al., Science 307, 1107 (2005).
10. J. Bremer et al., PloS One 4, e7160 (2009).
11. J. Hardy, D. J. Selkoe, Science 297, 353 (2002).
12. M. Sorandt, M. A. Mintun, D. Head, J. C. Morris, Arch
Neurol 66, 1476 (2009).
13. J. C. Morris et al., Arch Neurol 66, 1469 (2009).
14. S. X. Zhang-Nunes et al., Brain Pathology 16, 30 (2006).
15. L. C. Walker, H. LeVine, M. P. Mattson, M. Jucker,
Trends Neurosci 29, 438 (2006).
16. A. Aguzzi, L. Rajendran, Neuron 64, 783 (2009).
17. We thank M.-J. Runser, L. Jacobson (Basel), F. Langer, J.
Coomaraswamy, S. Grathwohl, N. Varvel, T. Hamaguchi,
C. Schäfer, A. Bosch, G. Frommer-Kästle, U. Scheurlen
(Tübingen) for experimental help and A. Aguzzi (Zürich)
for insightful comments. Supported by the Competence
Network on Degenerative Dementias (BMBF-01GI0705),
the BMBF in the frame of ERA-Net NEURON
(MIPROTRAN), the CIN (DFG), and NIH RR-00165.
Supporting Online Material
www.sciencemag.org/cgi/content/full/science.1194516/DC1
Materials and Methods
Fig. S1
References
1 July 2010; accepted 24 September 2010
Published online 21 October 2010; 10.1126/science.1194516
Fig. 1. Induced Aß deposition. (A and B) Aß-immunostained frontal cortex of Tg extract- (A) and Wt extract- (B) i.p. inoculated APP23 mice. (C and D) Most induced ß-amyloid was vascular (Aß-CAA), with Aß-immunoreactivity extending into the brain parenchyma (arrows). Amyloid-laden vessels were congophilic (red in D; birefringent under crosspolarized light, insert) and often were surrounded by diffuse, Congo red-negative Aß deposits (arrowheads). (E and F) Analysis of the entire neocortex for Aß-CAA frequency (indicated are all three [I-III] CAA severity grades [5]), and for total Aß load in Tg extract-inoculated mice compared to control (Ctr) mice. Cohort 1 consisted of 6 Tg extractinoculated mice vs. 7 untreated control mice. Aß-CAA: t(11) = 6.78 (all severity grades combined), ***P < 0.0001; Aß load: t(11) = 8.79, ***P < 0.0001. Cohort 2 consisted of 5 Tg extract-inoculated mice vs. 5 Wt extract-inoculated mice and 4 PBS-injected mice. These latter 2 (control) groups did not differ significantly, and were combined for analysis. Aß-CAA: t(12) = 7.79, ***P < 0.0001; Aß load t(12) = 2.71, *P < 0.05. The occasional parenchymal Aß-deposits in control mice are normal for 9-month-old APP23 mice. Indicated are means ±SEM. Scale bars: 200 µm (A,B); 50 µm (C,D).
Fig. 2. Induced Aß deposition was linked to multiple associated pathologies. (A) Ultrastructural analysis showed amyloid deposition within the vascular basal lamina (BL), with typical amyloid fibrils (arrowheads) extending into the brain parenchyma. Insets are low- and high-magnification views of the examined vessel (L = lumen) and the typical non-branching amyloid fibrils. (B to E) Vascular amyloid(stained by Congo Red in B and C) and parenchymal plaques were surrounded by hypertrophic, Iba1-positive microglia (B), GFAP-positive astrocytes (C), hyperphosphorylated taupositive neurites (D; asterisk indicates amyloid core), but a paucity of proximate neurons (cresyl-violet stain, E). (F and G) Vessels with CAA types II and III showed smooth muscle cell loss at the site of amyloid deposition (arrowheads; confocal image, maximum projection of 5 µm z-stack: red, Aß; green, smooth muscle actin). A normal vessel (G) has a complete ring of smooth muscle cells. (H) Immunoblotting of micropunches of Aß-immunoreactive material revealed the expected Aß band. Synthetic Aß40/42 is shown as control. Markers = 3 and 6 kD. Scale bars: 1 µm (A; insets 5 and 0.5 µm); 50 µm (B-E); 10 µm (F, G).
end...see ;
Peripherally Applied Aß-Containing Inoculates Induce Cerebral ß-Amyloidosis
http://www.sciencemag.org/cgi/content/abstract/science.1194516
BSE101/1 0136
IN CONFIDENCE
CMO
From: Dr J S Metters DCMO
4 November 1992
TRANSMISSION OF ALZHEIMER TYPE PLAQUES TO PRIMATES
http://collections.europarchive.org/tna/20081106170650/http://www.bseinquiry.gov.uk/files/yb/1992/11/04001001.pdf
CJD1/9 0185
Ref: 1M51A
IN STRICT CONFIDENCE
From: Dr. A Wight
Date: 5 January 1993
Copies:
Dr Metters
Dr Skinner
Dr Pickles
Dr Morris
Mr Murray
TRANSMISSION OF ALZHEIMER-TYPE PLAQUES TO PRIMATES
http://collections.europarchive.org/tna/20080102191246/http://www.bseinquiry.gov.uk/files/yb/1993/01/05004001.pdf
Friday, September 3, 2010
Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids, Prionpathy, Prionopathy, TSE
http://betaamyloidcjd.blogspot.com/2010/09/alzheimers-autism-amyotrophic-lateral.html
http://betaamyloidcjd.blogspot.com/
2010 PRION UPDATE
Thursday, August 12, 2010
Seven main threats for the future linked to prions
http://prionpathy.blogspot.com/2010/08/seven-main-threats-for-future-linked-to.html
http://prionpathy.blogspot.com/
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