The notion of "synaptic scaling" is consistent with the concept that functional capacity of synapses, as well as the presence or absence of synapses, is critical in the cognitive deficits of AD.

View all comments by Paul Coleman

This is a very interesting paper that describes a mechanism of synaptic scaling involving TNF-α. Synaptic scaling or compensation is an important phenomenon that is well recognized by neurophysiologists, but has been neglected in Alzheimer disease research. (See Turrigiano and Nelson, 2004, for an excellent review on this subject.) The pattern of retrograde amnesia that occurs in Alzheimer disease is best explained by a combination of synaptic dysfunction and synaptic scaling. (See Ruppin and Reggia, 1995; Small et al., 2001.) As boosting synaptic scaling may improve cognition (Small, 2004), the implication of the work in this paper is that glial TNF-α may by an important therapeutic target in Alzheimer disease research.

View all comments by David Small

David Small (1) reports that amnesia typical of that seen in AD can only be produced when synaptic scaling occurs, but suggests that it is a compensatory homeostatic mechanism. I would like to ask him whether it is possible that excessive synaptic scaling actually causes amnesia in AD?

Stellwagen and Malenka report that glial-derived TNFα modulates synaptic scaling. Giuliani and colleagues (2) report that interaction of activated T cells with microglia led to the substantial increase in TNFα levels which is inhibited by minocycline. CD82 (KAI1) is a target of APP, and CD82 is up-regulated on activated T cells (3). Might we suspect that overexpression APP may explain the activated T cells reported in AD? (4).

Of further interest is the study by Odintsova and colleagues (5) reporting that expression of CD82 coincides with increased surface expression of gangliosides GD1a and GM1.

Kakio et al. (6) report, "GM1 ganglioside-bound amyloid-β protein (GM1-Aβ), found in brains exhibiting early pathological changes of Alzheimer disease (AD) plaques, has been suggested to...  Read more

David Small (1) reports that amnesia typical of that seen in AD can only be produced when synaptic scaling occurs, but suggests that it is a compensatory homeostatic mechanism. I would like to ask him whether it is possible that excessive synaptic scaling actually causes amnesia in AD?

Stellwagen and Malenka report that glial-derived TNFα modulates synaptic scaling. Giuliani and colleagues (2) report that interaction of activated T cells with microglia led to the substantial increase in TNFα levels which is inhibited by minocycline. CD82 (KAI1) is a target of APP, and CD82 is up-regulated on activated T cells (3). Might we suspect that overexpression APP may explain the activated T cells reported in AD? (4).

Of further interest is the study by Odintsova and colleagues (5) reporting that expression of CD82 coincides with increased surface expression of gangliosides GD1a and GM1.

Kakio et al. (6) report, "GM1 ganglioside-bound amyloid-β protein (GM1-Aβ), found in brains exhibiting early pathological changes of Alzheimer disease (AD) plaques, has been suggested to accelerate amyloid fibril formation."

Schoenfeld et al. (7) report that CD82 activates Cdc42, which mediates GSH release and apoptosis induction.

It's of interest that Weggen and colleagues (8) report that ibuprofen suppressed AICD-mediated activation of the KAI1/CD82. Might a drug designed to specifically inhibit CD82 be beneficial in AD, and might some of the side effects of NSAIDS then be avoided?

References:
1. Small DH. Mechanisms of synaptic homeostasis in Alzheimer's disease. Curr Alzheimer Res. 2004 Feb;1(1):27-32. Review. Abstract

2. Giuliani F, Hader W, Yong VW. Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell-microglia interaction. J Leukoc Biol. 2005 Jul;78(1):135-43. Epub 2005 Apr 7. Abstract

3. Shibagaki N, Hanada K, Yamashita H, Shimada S, Hamada H. Overexpression of CD82 on human T cells enhances LFA-1 / ICAM-1-mediated cell-cell adhesion: functional association between CD82 and LFA-1 in T cell activation. Eur J Immunol. 1999 Dec;29(12):4081-91. Abstract

4. Town T, Tan J, Flavell RA, Mullan M. T-cells in Alzheimer's disease. Neuromolecular Med. 2005;7(3):255-64. Review. Abstract

5. Odintsova E, Voortman J, Gilbert E, Berditchevski F. Tetraspanin CD82 regulates compartmentalisation and ligand-induced dimerization of EGFR. J Cell Sci. 2003 Nov 15;116(Pt 22):4557-66. Abstract

6. Kakio A, Nishimoto S, Yanagisawa K, Kozutsumi Y, Matsuzaki K. Interactions of amyloid beta-protein with various gangliosides in raft-like membranes: importance of GM1 ganglioside-bound form as an endogenous seed for Alzheimer amyloid. Biochemistry. 2002 Jun 11;41(23):7385-90. Abstract

7. Schoenfeld N, Bauer MK, Grimm S. The metastasis suppressor gene C33/CD82/KAI1 induces apoptosis through reactive oxygen intermediates. FASEB J. 2004 Jan;18(1):158-60. Epub 2003 Nov 3. Abstract

8. Weggen S, Eriksen JL, Sagi SA, Pietrzik CU, Golde TE, Koo EH. Abeta42-lowering nonsteroidal anti-inflammatory drugs preserve intramembrane cleavage of the amyloid precursor protein (APP) and ErbB-4 receptor and signaling through the APP intracellular domain. J Biol Chem. 2003 Aug 15;278(33):30748-54. Epub 2003 May 31. Abstract

View all comments by Mary Reid

I agree with the comments of Paul Coleman and David Small. Changes in TNF-mediated synaptic scaling may help explain the clinical results of the pilot study we recently published, which suggest that perispinal administration of etanercept, a biologic TNF antagonist, may hold promise as a potential treatment modality for Alzheimer's disease (see TNFα modulation for treatment of Alzheimer's disease: A 6 month pilot study, Medscape General Medicine, 2006. 8(2):25; see full text.

View all comments by E T