Elsevier

Progress in Neurobiology

Volume 55, Issue 6, 1 August 1998, Pages 659-669
Progress in Neurobiology

Cell adhesion molecules in neural plasticity and pathology: similar mechanisms, distinct organizations?

https://doi.org/10.1016/S0301-0082(98)00025-2Get rights and content

Abstract

Brain plasticity and the mechanisms controlling plasticity are central to learning and memory as well as the recovery of function after brain injury. While it is clear that neurotrophic factors are one of the molecular classes that continue to regulate brain plasticity in the adult central nervous system (CNS), less appreciated but equally profound is the role of cell adhesion molecules (CAMs) in plasticity mechanisms such as long term potentiation, preservation of neurons and regeneration. Ironically, however, CAMs can also reorganize the extra-cellular space and cause disturbances that drive the development of brain pathology in conditions such as Alzheimer's disease and multiple sclerosis. Candidate molecules include the amyloid precursor protein which shares many properties of a classical CAM and β-amyloid which can masquerade as a pseudo CAM. β-Amyloid serves as a nidus for the formation of senile plaques in Alzheimer's disease and like CAMs provides an environment for organizing neurotrophic factors and other CAMs. Inflammatory responses evolve in this environment and can initiate a vicious cycle of perpetuated neuronal damage that is mediated by microglia, complement and other factors. Certain CAMs may converge on common signal transduction pathways involving focal adhesion kinases. Thus a breakdown in the organization of key CAMs and activation of their signal transduction mechanisms may serve as a new principle for the generation of brain pathology.

Introduction

The mechanisms that regulate the development and plasticity of the nervous system are traditionally viewed as separate from those that drive the evolution of brain pathology and disease. It is well known, for example, that neurotrophic factors are critical for the development, maintenance and plasticity of the nervous system. It is becoming increasingly clear that cell adhesion molecules (CAMs) also regulate neuronal development, maintenance and plasticity. Together these are primary extracellular signaling systems controlling such functions. Because these molecular systems are so important it is likely that some mechanisms may exist which can generate dysfunction.

In this article we will discuss the role of various cell adhesion molecules in brain plasticity in the adult nervous system and conversely explore the hypothesis that cell adhesion molecules (or pseudo cell adhesion molecules) can contribute to the development of age-related pathology, particularly in Alzheimer's disease (AD). We have focused the discussion on cell adhesion molecules because their role in this type of mechanism is only beginning to be recognized. In Section 2, the discussion is directed toward the normal function of select cell adhesion molecules and how they can participate in long-term potentiation (LTP) mechanisms, strengthen synapses, and ultimately stimulate additional growth in the mature nervous system. In addition to more conventional molecules such as the neural cell adhesion molecule (NCAM), recent data show that the amyloid precursor protein (APP) can participate in cell surface interactions; mutations in APP have also recently been described to affect plasticity mechanisms, such as LTP and spatial learning. In turn, alterations in neurotrophin expression may in fact reinforce the production of cell adhesion molecules, indicating that there is convergence of plasticity mechanisms.

In Section 3we will discuss the role of adhesion molecules in repair and eventual development of pathology. In the repair process, cell adhesion molecules are well known to guide regenerative growth responses. In addition, surface interactions have a role in the development of pathology as, for example, the APP, which accumulating evidence indicates is involved in cell adhesion and stabilization of adhesion sites. APP can interact with other cell adhesion proteins, such as the extracellular matrix molecule laminin. Finally, molecules that are not normally considered adhesion proteins may share similar properties. For example, β-amyloid bound to the surface or placed in aggregated forms will attract neurites and act as an adhesion surface, however, when it is aggregated over time the neurites will degenerate. In AD, β-amyloid acts both as a substrate and participates in the organization of other substrates and adhesion molecules in the form of senile plaques. We suggest that the plaque actually forms a local abnormal micro-environment that employs some of the same principles that are used during normal growth and development. This may appear paradoxical but could occur if there is a breakdown of organization and spatial relationships. We will then focus on the involvement of microglial cells in repair and pathology in the CNS and discuss the possible role of microglial adhesion molecules as mediators of cell–cell- and cell–matrix-interactions.

In Section 4we will illustrate how some of these extracellular mechanisms may be unified by common convergent signal transduction pathways, possibly mediated by focal adhesion kinases (FAK) merging into other intracellular second messenger systems. These can be involved in growth stabilization; but there is growing evidence that they can activate programmed cell death, so that the same convergent pathway can either serve to regulate growth mechanisms or participate in the destruction of the cell.

While the above discussion is focused on neurons and their interaction, the same perspective can in many ways be developed from the point of view of the microglial cell. Microglial cells represent a brain-based system of phagocytic, fully immunocompetent cells that are activated in most central nervous system (CNS) pathologies, taking part in the removal of degenerating neurons or non-neuronal cells. Recent work shows that microglia alter the expression of their cell adhesion molecules when activated. This phenomenon probably has a role in homo- and hetero-meric interactions of microglia with their local micro-environments. Thus, cell adhesion molecules may be key molecular determinants in the response of the nervous system to injury, using common molecular mechanisms but different signal systems and in different spatial organizations.

Section snippets

The role of adhesion molecules in non-pathological plasticity of excitatory and inhibitory synapses

Adhesion molecules are ligands and receptors that mediate cell–cell- or cell–matrix-interactions by lock and key recognition and subsequently relay to the cell interior [see Wheal et al. (1998); Goodman (1996)]. There are several key classes including the immunoglobulin supergene-family [NCAM, intercellular adhesion molecule (ICAM), Thy-1], integrins (b1: VLA-4, b2: LFA-1, Mac-1) and selectins (E-, L- and P-selectin) (Fig. 1).

Changes in synaptic efficacy are likely to involve alterations of the

Cell adhesion molecules in repair vs the development of pathology

Cell adhesion molecules have a well documented role in developmental and regenerative growth responses in the CNS. In the dentate gyrus, for example, after entorhinal lesions NCAM is induced over the entire dendritic surface of the granule cells within the first day and then becomes restricted to the outer dendritic field where new synapses are forming (Miller et al., 1994). Such mechanisms appear critical in the spatial and temporal responses for regrowth and remodeling of neuronal circuits.

Integrins and NCAMs are coupled to intracellular signal transduction pathways via focal adhesion kinases

As discussed above identification of the signal transduction pathways activated by CAMs will provide important insights into mechanisms placing cells at risk. CAMs such as integrins serve the dual function of cell adhesion and signal transduction (Otey, 1996; Parsons and Parsons, 1997; Hanks and Polte, 1997) and are mediated by common signaling pathways. Integrins mediate the effect of extracellular effectors by linking to the F-actin cytoskeleton via a large protein complex, the focal adhesion

Summary and conclusion

In this article we have presented the hypothesis that cell adhesion molecules are critical participants in the maintenance and plasticity of the mature brain as exemplified by their role in LTP at both excitatory and inhibitory synapses. Recent evidence suggests that different cell adhesion molecules may in fact serve excitatory (NCAM) vs inhibitory (Thy-1) systems and thus (similar to neurotrophic factors) cell adhesion molecules may exhibit synapse specificity.

Cell adhesion molecules and

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