At first glance, these intriguing results seem to suggest that overall intracranial Aß levels might be the relevant factor in determining whether amyloid deposition occurs. Indeed, this idea fits well with accumulating evidence that peripheral antibodies or other Aß-binding molecules such as gelsolin can—by "pulling" Aß across the blood-brain barrier through a mechanism resembling dialysis—effectively prevent amyloid deposition by lowering intracranial Aß levels (e.g., DeMattos et al., 2001; Matsuoka et al., 2003). However, Meyer-Luehmann and colleagues go on to show that the likelihood of amyloid deposition is influenced at a still more local level, since grafts transplanted into brain subregions with relatively high Aß levels (e.g., hippocampus) show amyloid deposition more often than do grafts in brain regions with lower Aß levels (e.g., striatum). These data appear to point to the presence of concentration gradients of Aß within the cerebrum, and raise several important questions. What is the nature of the "sinks" within the brain that are responsible for Aß removal? Could shunts provide an artificial means of lowering intracranial Aß levels? Whatever the answer to these questions, this paper provides further evidence that mechanisms of Aß removal are at least as important as those of Aß production in determining amyloid pathology. The neural graft paradigm may provide an elegant way to test some of these fundamental questions.—Malcolm Leissring, Brigham and Women’s Hospital, Boston, Massachusetts.

References:

Meyer-Luehmann M, Stalder M, Herzig MC, Kaeser SA, Kohler E, Pfeifer M, Boncristiano S, Mathews PM, Mercken M, Abramowski D, Staufenbiel M, Jucker M. Extracellular amyloid formation and associated pathology in neural grafts. Nat Neurosci. 2003 Feb 24;[epub ahead of print]

DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8850-5. Abstract

Matsuoka Y, Saito M, LaFrancois J, Saito M, Gaynor K, Olm V, Wang L, Casey E, Lu Y, Shiratori C, Lemere C, Duff K. Novel therapeutic approach for the treatment of Alzheimer's disease by peripheral administration of agents with an affinity to beta-amyloid. J Neurosci. 2003 Jan 1;23(1):29-33. Abstract

View all comments by Malcolm Leissring

Nevertheless, I wonder how the investigators were able so precisely to demarcate graft versus host tissue. Their observation that plaques develop at the periphery of grafts could also suggest that plaques occur in injured host tissue just outside the margins of the graft. Indeed,...  Read more

Nevertheless, I wonder how the investigators were able so precisely to demarcate graft versus host tissue. Their observation that plaques develop at the periphery of grafts could also suggest that plaques occur in injured host tissue just outside the margins of the graft. Indeed, injury and/or inflammation are associated with increased plaque formation and could explain why the injured transgenic host tissue develops more extensive plaques. The needle stab control was one of their attempts to explore this possibility.

Overall, the paper provides a unique approach to investigate plaque formation in AD. Unfortunately, it again moves us away from what appeared to be an evolving consensus (see recent Alzforum chat) for a critical role of both extracellular and intracellular β-amyloid in plaque formation back to one favoring mainly extracellular β-amyloid, though this is unlikely to be the final chapter in this now century-old debate on the origin of plaques.

View all comments by Gunnar K. Gouras

Comment by Berislav Zlokovic—Posted 5 March 2003.
The paper by Meyer-Leuchmann et al. uses transplant biology to provide convincing evidence that CNS transport of soluble Aß is a major factor implicated in amyloid formation and neurotoxicity. The significant delay in amyloid deposits in AßPP23 cellular neuronal embryonic grafts in wild-type hosts versus AßPP23 hosts, and the development of amyloid in wild-type neuronal grafts in AßPP23 host, are highly suggestive that extracellular factors and CNS transport play a primary role in regulating brain Aß levels and amyloid deposition. To give a different flair on this study from an alternative "vasculocentric" view, the altered vascular biology could also be a contributory factor in the "transplant" paradigm. Namely, wild-type grafts in AßPP23 hosts at the time of grafting (six months) are neovascularized by AßPP-primed vasaculature, while AßPP23 grafts in wild-type hosts are neovascularized by healthy host vascular cells. Since the vascular system plays an important role in brain efflux of Aß, as well as in the influx...  Read more

Comment by Berislav Zlokovic—Posted 5 March 2003.
The paper by Meyer-Leuchmann et al. uses transplant biology to provide convincing evidence that CNS transport of soluble Aß is a major factor implicated in amyloid formation and neurotoxicity. The significant delay in amyloid deposits in AßPP23 cellular neuronal embryonic grafts in wild-type hosts versus AßPP23 hosts, and the development of amyloid in wild-type neuronal grafts in AßPP23 host, are highly suggestive that extracellular factors and CNS transport play a primary role in regulating brain Aß levels and amyloid deposition. To give a different flair on this study from an alternative "vasculocentric" view, the altered vascular biology could also be a contributory factor in the "transplant" paradigm. Namely, wild-type grafts in AßPP23 hosts at the time of grafting (six months) are neovascularized by AßPP-primed vasaculature, while AßPP23 grafts in wild-type hosts are neovascularized by healthy host vascular cells. Since the vascular system plays an important role in brain efflux of Aß, as well as in the influx of circulating Aß into the CNS, this systemic vascular factor may well work in favor of early deposition of Aß in wild-type grafts in AßPP23 hosts, and delayed deposition into AßPP23 grafts in wild-type hosts. Once AßPP23 grafts in wild-type hosts change the host vascular system into one of the AßPP23 types, the pendulum swings back, leading to amyloid accumulation in the graft.

View all comments by Berislav Zlokovic

Conversely, in a nontransgenic host, the Aβ formed within a transgenic graft flows out of the graft and becomes so diluted in the surrounding tissue that, in most instances, neither graft nor host brain is sullied by deposits. The idea has been around for years that lowering the local concentration of amyloidogenic proteins can reduce their tendency to aggregate, but the results from the Jucker lab add weight to the argument that simply augmenting a concentration gradient (e.g., by immunotherapy or CSF shunting) could have therapeutic benefit. Enhancing removal of Aβ by stimulation of intracellular degradation or active transcytosis also has been suggested. Indeed, the Basel group found that grafts into the transgenic striatum, an area that produces less Aβ than does cortex and hippocampus, are much less likely to develop deposits, indicating that a relatively small reduction in local Aβ concentration may be sufficient to impede the pathogenic cascade.

What is next? Part of the value of these experiments (in addition to the considerable effort that went into their execution) is their attempt to explain β-amyloidogenesis in the complex environment of the brain. Not unexpectedly, additional questions arise that might be addressed in the graft model. For example, the authors note the presence of acetylcholinesterase-positive neurites around some plaques; many of the cholinesterase-positive axons in neocortex and hippocampus arise from the cholinergic neurons of the basal forebrain cholinergic system, although cholinesterase is not specific to cholinergic cells. What is the origin of these neurites? Ingrowing axons, or some intragraft source? Is there evidence of stem cell-related activity in or near the grafts? And how do the cellular populations in the grafts (which appear to be largely self-contained) relate to the normal makeup of the host tissue? Specifically, has there been phenotypic drift in neuronal transmitter specificities, for example, and does this influence the pathological response of the graft? How would grafts from plaque-resistant brain areas such as cerebellum or striatum fare in the cortex or hippocampus of a transgenic host (i.e., are there region-specific features that render these areas resistant to amyloidogenesis)? The grafting model described by Meyer-Luehmann and colleagues presents promising new opportunities for applying the important lessons we have learned from molecular and cellular studies of β-amyloidogenesis to the milieu in which it matters most—the living brain.

View all comments by Lary Walker

A superficial interpretation of the above findings would be that intracellular production and accumulation of Aß does not contribute to the pathology caused by this peptide. This interpretation, however, runs counter to accumulating evidence. As summarized in the report by Meyer-Luehmann et al., both in vitro and in vivo investigations have indicated that at least one pool of Aß is produced intracellularly, and appears to accumulate in neurons. Accumulation of Aß in cortical pyramidal and nonpyramidal neurons has been reported in normal elderly individuals (4), Alzheimer’s disease (AD) (2,5), individuals with mild cognitive impairment (4), Down’s syndrome (6), and in AßPP-presinilin-1 transgenic animals (9). Significantly, intracellular accumulation of neuronal Aß in many of the above models precedes the formation of plaques.

It is quite likely that accumulation of high concentrations of intracellular Aß exerts detrimental effects on neurons. Consistent with this possibility, expression of high levels of intracellular Aß have been implicated in damage to neurons and other cells (1,2,7). Microinjection of Aß-42 or cDNA expressing cytosolic Aß-42 into cultured primary human neurons resulted in rapid and selective cell death (11). In normal elderly individuals and particularly those with AD, intraneuronal Aß has been shown to accumulate in multivesicular bodies localized in synapses, and to be associated with synaptic pathology (8). Of particular interest, recent evidence suggests that intraneuronal Aß may form aggregates and cause lysis of neurons, leading to an extracellular deposit (2,4). Thus, in addition to its likely deleterious effects on neurons, intraneuronal Aß may serve as one source of Aß deposited in plaques.

Based on the evidence for the abnormal effects of both accumulated intracellular Aß and extracellularly deposited Aß, we have proposed a hypothetical two-component model of Aß pathology in AD (see Alzforum live discussion). According to this model, early accumulation of Aß in neurons represents the first component of Aß pathology and causes neuronal and synaptic dysfunction, and perhaps neuronal loss. Extracellular deposition of Aß in plaques, which, as demonstrated by Meyer-Luehmann et al., need not be related to intraneuronal accumulation of Aß, represents the second component and exerts toxic effects on neurons and processes.—Changiz Geula, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Reference:
1. Fresh and globular amyloid beta protein (1-42) induces rapid cellular degeneration: evidence for AbetaP channel-mediated cellular toxicity. FASEB J. 2000 Jun;14(9):1233-43. Abstract

2. Evidence that neurones accumulating amyloid can undergo lysis to form amyloid plaques in Alzheimer's disease. Histopathology. 2001 Feb;38(2):120-34. Abstract

3. Geula C, Wu CK, Saroff D, Lorenzo A, Yuan M, Yankner BA. Aging renders the brain vulnerable to amyloid beta-protein neurotoxicity. Nat Med. 1998 Jul;4(7):827-31. Abstract

4. Gouras GK, Tsai J, Naslund J, Vincent B, Edgar M, Checler F, Greenfield JP, Haroutunian V, Buxbaum JD, Xu H, Greengard P, Relkin NR. Intraneuronal Abeta42 accumulation in human brain. Am J Pathol. 2000 Jan;156(1):15-20. Abstract

5. Mochizuki A, Tamaoka A, Shimohata A, Komatsuzaki Y, Shoji S. Abeta42-positive non-pyramidal neurons around amyloid plaques in Alzheimer's disease. Lancet. 2000 Jan 1;355(9197):42-3. Abstract

6. Mori C, Spooner ET, Wisniewsk KE, Wisniewski TM, Yamaguch H, Saido TC, Tolan DR, Selkoe DJ, Lemere CA. Intraneuronal Abeta42 accumulation in Down syndrome brain. Amyloid. 2002 Jun;9(2):88-102. Abstract

7. Querfurth HW, Suhara T, Rosen KM, McPhie DL, Fujio Y, Tejada G, Neve RL, Adelman LS, Walsh K. Beta-amyloid peptide expression is sufficient for myotube death: implications for human inclusion body myopathy. Mol Cell Neurosci. 2001 May;17(5):793-810. Abstract

8. Takahashi RH, Milner TA, Li F, Nam EE, Edgar MA, Yamaguchi H, Beal MF, Xu H, Greengard P, Gouras GK. Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol. 2002 Nov;161(5):1869-79. Abstract

9. Wirths O, Multhaup G, Czech C, Blanchard V, Moussaoui S, Tremp G, Pradier L, Beyreuther K, Bayer TA. Intraneuronal Abeta accumulation precedes plaque formation in beta-amyloid precursor protein and presenilin-1 double-transgenic mice. Neurosci Lett. 2001 Jun 22;306(1-2):116-20. Abstract

10. Yankner BA. Mechanisms of neuronal degeneration in Alzheimer's disease. Neuron. 1996 May;16(5):921-32. Review. No abstract available. Abstract

11. Zhang Y, McLaughlin R, Goodyer C, LeBlanc A. Selective cytotoxicity of intracellular amyloid beta peptide1-42 through p53 and Bax in cultured primary human neurons. J Cell Biol. 2002 Feb 4;156(3):519-29. Abstract

View all comments by Changiz Geula