Michael R. D'Andrea

Michael R. D'Andrea led this live discussion on 4 December 2003. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

View Transcript of Live Discussion — Posted 26 August 2006

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By Michael R. D'Andrea

In brief, highly significant increases of immunoglobulins (Igs) were detected in entorhinal cortex and hippocampal parenchyma of AD cases as compared to age-matched, nondemented control brain tissues. These Igs were associated with vessels in the AD brain tissues. In areas with greater parenchymal Ig reactivity, the number of Ig-positive neurons was also dramatically increased. The Ig labeling extended throughout the neurons, which showed neurodegenerative and apoptotic features that were not observed in Ig-negative neurons or in Ig-positive astrocytes.

Therefore, the loss of neurons observed in AD brain may be dependent on the presence, as well as the affinity/avidity, of neuron-specific autoantibodies in conjunction with a BBB dysfunction. In my view, the confluence of these two factors represents an important part of AD neuropathology. The more compromised the BBB is (and, incidentally, damage to the BBB may be a major contribution of amyloid to AD pathogenesis), the more neuron-specific Igs (if present in the serum) could pass into the brain parenchyma and gain access to their autoantigens. I hypothesize that once they bind to their targets, the neuron dies. Thus, the presence of Ig-positive neurons in AD brains implies a critical link between the two well-established factors of a faulty BBB and neuronal death through an autoimmune mechanism.

This is the first time AD has been demonstrated to be an autoimmune disease. I hope this benchmark study will stimulate interest so that others will test my findings and discover the autoantigen(s). I also hope scientists will consider adapting current therapies of other CNS autoimmune diseases (e.g., plasma exchange therapy used for Rasmussen's encephalitis) to AD. Finally, efforts to intervene at the BBB level to restrict serum Igs from penetrating the brain should be revitalized.

Let's discuss these questions:

What other experiments are needed to give this hypothesis more credence?

How do we discover the antigen?

What happens in the neuron after the antibodies bind?

Can this be modeled in cultured rat or mouse brain slices?

Can Ig binding to a neuron cause its degeneration, or is it a nonspecific late event?

How does this hypothesis intersect with T cells? (see Monsonego et al., 2003).

Do people who died of stroke and other forms of dementia also have these antibodies?

References:
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Fullerton SM, Shirman GA, Strittmatter WJ, Matthew WD. Impairment of the blood-nerve and blood-brain barriers in apolipoprotein E knockout mice. Exp Neurol. 2001 May;169(1):13-22. Abstract

Mooradian AD. Effect of aging on the blood-brain barrier. Neurobiol Aging 9 (1998) 31-39. Abstract

Pappolla MA, Andorn AC. Serum protein leakage in aged human brain and inhibition of ligand binding at α 2-adrenergic and cholinergic binding sites. Synapse. 1987;1(1):82-9. Abstract

Watts H, Kennedy PG, Thomas M. The significance of antineuronal antibodies in Alzheimer's disease. J Neuroimmunol. 1981 Mar;1(1):107-16. Abstract

Chapman J, Bachar O, Korczyn AD, Wertman E, Michaelson DM. Antibodies to cholinergic neurons in Alzheimer's disease. J Neurochem. 1988 Aug;51(2):479-85. Abstract

de la Torre JC, Stefano GB. Evidence that Alzheimer's disease is a microvascular disorder: the role of constitutive nitric oxide. Brain Res Brain Res Rev. 2000 Dec;34(3):119-36. Review. Abstract

Gomez-Isla T, West HL, Rebeck GW, Harr SD, Growdon JH, Locascio JJ, Perls TT, Lipsitz LA, Hyman BT. Clinical and pathological correlates of apolipoprotein E ε4 in Alzheimer's disease. Ann Neurol. 1996 Jan;39(1):62-70. Abstract

Plateel M, Teissier E, Cecchelli R. Hypoxia dramatically increases the nonspecific transport of blood-borne proteins to the brain. J Neurochem. 1997 Feb;68(2):874-7. Abstract

Rogers SW, Andrews PI, Gahring LC, Whisenand T, Cauley K, Crain B, Hughes TE, Heinemann SF, McNamara JO. Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis. Science. 1994 Jul 29;265(5172):648-51. Abstract

Esch T, Stefano G. Proinflammation: a common denominator or initiator of different pathophysiological disease processes. Med Sci Monit. 2002 May;8(5):HY1-9. Review. Abstract

Mehta PD, Dalton AJ, Mehta SP, Percy ME, Sersen EA, Wisniewski HM. Immunoglobulin G subclasses in older persons with Down syndrome. J Neurol Sci. 1993 Jul;117(1-2):186-91. Abstract

D'Andrea MR. Add Alzheimer's disease to the list of autoimmune diseases. Med Hypotheses. 2005; 64(3):458-63. Abstract.

	Comments on Live Discussion
	Comment by:  Marie Sanchirico
	Submitted 3 December 2003  |  Permalink	Posted 3 December 2003
	The selective presence of large numbers of Ig+-neurons and their association with an apoptotic phenotype in AD brain tissue versus healthy controls is very interesting, and certainly suggests a possible B cell-mediated autoimmune component to disease. An important question is whether there is increased Ig+ labeling of pyknotic neurons in the few APP mouse models that exhibit minor neuronal death in the CA1 region? The notion that AD pathology is in part driven by an immune mechanism has been hypothesized for more than a decade due to differences in effector cell ratios in the plasma of AD patients versus controls. This theory has gained momentum in the last few years thanks to an increased understanding of what drives chronic inflammation, but appropriate animal models are clearly needed to dissect the exact contributions of both the innate and acquired immune system in AD. Currently, the role of the immune system is being addressed in existing APP Tg models by selective deletion of individual effector cell populations. The major barrier to definitively...  Read more The selective presence of large numbers of Ig+-neurons and their association with an apoptotic phenotype in AD brain tissue versus healthy controls is very interesting, and certainly suggests a possible B cell-mediated autoimmune component to disease. An important question is whether there is increased Ig+ labeling of pyknotic neurons in the few APP mouse models that exhibit minor neuronal death in the CA1 region? The notion that AD pathology is in part driven by an immune mechanism has been hypothesized for more than a decade due to differences in effector cell ratios in the plasma of AD patients versus controls. This theory has gained momentum in the last few years thanks to an increased understanding of what drives chronic inflammation, but appropriate animal models are clearly needed to dissect the exact contributions of both the innate and acquired immune system in AD. Currently, the role of the immune system is being addressed in existing APP Tg models by selective deletion of individual effector cell populations. The major barrier to definitively defining the exact contribution of the immune system in AD is the appropriateness of these models, in particular the lack of neuronal loss. If, as this paper suggests, the immune system is ultimately responsible for specific neuronal loss, ablation of immune components in these models might not shed light on an autoimmune mechanism. Identification of neuronal autoantigens may allow deliberate design of AD models and/or induction of disease. View all comments by Marie Sanchirico

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