Alzheimer’s disease as a disorder of dynamic brain self-organization

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Abstract

Mental function is based on the dynamic organization of neuronal networks. In particular, phylogenetically young brain areas (e.g., cortical associative circuits), involved in the realization of “higher brain functions” such as learning, memory, perception, self-awareness, and consciousness, are continuously re-adjusted even after development is completed. By this life-long self-optimization process, epigenetic information remodels the cognitive, behavioral and emotional reactivity of an individual to meet the environmental demands. To organize brain structures of increasing complexity during evolution, the process of selective dynamic stabilization and destabilization of synaptic connections becomes more and more important. The mechanisms of structural stabilization and labilization underlying a lifelong synaptic remodeling according to experience, are accompanied, however, by an increasing inherent potential of failure and may, thus, not only allow for the evolutionary acquisition of “higher brain function” but at the same time may provide the basis for selective neuronal vulnerability. The mechanisms of synaptic plasticity, i.e., of modifiable interneuronal connectivity, are largely based on external morphoregulatory cues and internal signaling pathways that nonneuronal cells have phylogenetically acquired to sense their relationship to the local neighborhood and to control proliferation and differentiation in the process of tissue repair and regeneration after development is completed. Differentiated neurons that have withdrawn from the cell cycle use these molecular machinery alternatively to control synaptic plasticity. The existence of these alternative effector pathways within a neuron puts it on the risk to erroneously convert signals derived from plastic synaptic changes into positional cues that will activate the cell cycle. This cell cycle activation potentially links synaptic plasticity to cell death. Preventing cell cycle activation by locking neurons in a differentiated but still highly plastic phenotype will, thus, be crucial to prevent neurodegeneration.

Section snippets

Self-organization of plastic brain structure

The structural building of the mammalian brain and its maintenance requires a balanced instruction through both genetic and epigenetic information. The human brain consists of about 1012 neurons with each neuron receiving about 104 to 105 synaptic contacts. For comparison, the human genome contains less than 100,000 genes. Therefore, genetic instructions alone are apparently not sufficient to structurally organize such a highly complex organ as the mammalian brain. Algorithms of brain

Plasticity “creates” vulnerability

Adaptive reorganization of neuronal connectivity which allows for the acquisition of new epigenetic information both during development and in the mature brain is based upon the strengthening of existing synapses, the formation of new synapses and the destabilization of previously established synaptic contacts. To organize brain structures of increasing complexity during evolution, these processes of dynamic stabilization and destabilization might become more and more important and particularly

The hierarchical pattern of pathology in AD follows the pattern of plasticity

Neurofibrillary degeneration in the cerebral cortex shows a significant association with dementia severity (Arriagada et al., 1992) as well as with metabolic indicators of neurodegeneration (DeCarli et al., 1992). Neurofibrillary tangles (NFT), however, are not evenly distributed throughout the brain. Simchowicz who in 1911 emphasized the Ammon's horn as the area of predilection for neurofibrillary changes clearly recognized that the distribution of neuropathological lesions in AD favors

The ontogenetic and phylogenetic dimension — “last in–first out”

The pattern of progressive neurofibrillary changes, the pattern of neuronal losses, and other indicators of degeneration such as cerebral glucose metabolic decrement show some remarkable resemblance to both phylogenetic and ontogenetic development (Spatz, 1925), i.e., the developmentally young areas and those that mature very late in ontogenetic development are most sensitive [“last in–first out”] (McGeer et al., 1990; Braak and Braak, 1996) (Fig. 3, Fig. 4).

Consistent with the late

Functional disease progression inversely corresponds to developmental sequences

If neurodegeneration in AD follows a certain hierarchy affecting the ontogenetically and phylogenetically most recent areas of the central nervous system most severely (Spatz, 1925), one might also expect a hierarchy of mental dysfunction related to both ontogeny and phylogeny. Indeed, there exists a relationship between cognitive, language, praxic and other functional changes in the course of AD and inversely corresponding to developmental sequences.

The decline in dementia in certain

Morphodysregulation and aberrant structural plasticity in AD

Synaptic loss in the hippocampus and neocortex is an early change and the major structural correlate of cognitive dysfunction as corroborated by a variety of electron microscopic, immunocytochemical and biochemical studies on synaptic marker proteins in AD biopsies and autopsies (Table 2) (Gibson, 1983; Scheff et al., 1990; Terry et al., 1991). Synaptic pathology is reflected by a loss of all major components of small synaptic vesicles and most peptides, stored in large dense core vesicles

Morphoregulatory molecules in Alzheimer’s disease and other neurodegenerative disorders

A disturbance of brain self-organization that becomes manifest in the adult brain might involve morphoregulatory molecules, i.e., molecules that are developmentally regulated and are expressed in the adult brain mainly in areas that retain a high neuroplastic potential. According to the necessity of synaptic turnover and reorganization, growth cone and synaptic properties might overlap to some degree and the preservation of these properties might allow for synaptic plasticity in the adult

Replay of developmental mechanisms as an end stage of a slowly progressing “morpho-dysregulation”

The aberrant neuritic growth in AD, as a likely indication of defect synapse turnover, is accompanied by microtubular re-organization (McKee et al., 1989) associated with the re-expression of a number of developmentally regulated proteins involved in morphoregulation in particular cell-adhesion proteins as for example PSA-NCAM (Jorgensen and Balázs, 1993; Mikkonen et al., 1999) and cytoskeletal proteins such as the fetal form of alpha-tubulin and MAP5 (MAP1B) (Geddes et al., 1990; Hasegawa et

Mitogenic signal transduction in Alzheimer’s disease

The presence in the AD brain of growth-associated proteins, such as GAP43, MARCKS, spectrin, heparansulfate, laminin, NCAM, various cytokines and neurotrophic factors such as NGF, bFGF, EGF, IL-1, IL-2, IL-6, IGF-1, IGF-2, PDGF and HGF/SF as well as growth factor receptors might be an indication of an increased trophic force particularly pronounced within the microenvironment of plaques (for review see Arendt, 2003, see also Table 3).

Mitogenic effects of these compounds are intracellularly

The small G-protein p21ras

Proliferative and growth stimulating effects of a number of growth factors that are elevated in early stages of AD are mediated by the activation of the MAPK pathway which is also involved in modulating the expression and posttranslational processing of APP and tau protein (Greenberg et al., 1994; Cosgaya et al., 1996; Mills et al., 1997; Desdouits-Magnen et al., 1998). The activation of cell surface receptors of trophic and mitogenic factors is relayed to the downstream MAPK cascade by the

Nitric oxide and the process of self-perpetuation of neurodegeneration

p21ras is also activated by nitric oxide (NO) and intermediates generated through oxidative stress. (Yun et al., 1998). Thus, NO might be a key mediator linking cellular activity to gene expression and long lasting neuronal responses through activating p21ras by redox sensitive modulation. In AD, nNOS, the neuron-specific NO synthesizing enzyme is aberrantly expressed in potentially vulnerable neurons of the isocortex and entorhinal cortex. Since these neurons express nNOS prior to their

Mitogen-activated-protein-kinase cascade

The MAPKs or extracellular signal regulated kinases (ERKs) and MAPKK or MAP/ERK kinase (MEK) belong to a group of protein kinases which is highly conserved from yeast to vertebrates (Boulton et al., 1990). They are key molecules in signal processing that become activated in response to a wide variety of reagents. Among these are tumour promotors, interleukins, growth factors whose receptors are tyrosine kinases, mitogens whose receptors couple to heterotrimeric guanine nucleotide binding

Loss of cell cycle control and dedifferentiation in Alzheimer’s disease

The data presented here suggest that the activation of the p21ras/MAPK cascade that plays an essential role in transmitting proliferative responses is also involved in early steps of the pathomechanism of AD. The induction of cell proliferation by MAP kinase has been shown to be a direct result of increased transcription of many immediate early genes (Seth et al., 1992) including cyclin D1. In transforming cells, moreover, p21 ras is involved in the regulation of the G0/G1 transition of the

Conclusions

Taken together, in multicellular organisms, cell number is regulated spatially by extracellular signals through cell interactions controlling proliferation and survival in local neighborhoods. Epigenetic instructions from neighboring cells can induce cell proliferation, differentiation or death. These stimuli include cell–cell and cell–ECM adhesion, growth factors, cytokines, neuropeptides and mechanical factors. Signals from G-protein-coupled receptors, tyrosine kinase receptors and integrins

Acknowledgements

This paper is based on studies that were supported by the Bundesministerium für Bildung, Forschung und Technologie (BMBF), Interdisziplinäres Zentrum für Klinische Forschung (IZKF) at the University of Leipzig (01KS9504, Project C1) and the European Commission (QLK6-CT-1999-02112).

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