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Modelling the formation of working memory with networks of integrate-and-fire neurons connected by plastic synapses.

In this paper we review a series of works concerning models of spiking neurons interacting via spike-driven, plastic, Hebbian synapses, meant to implement stimulus driven, unsupervised formation of working memory (WM) states. Starting from a summary of the experimental evidence emerging from delayed matching to sample (DMS) experiments, we briefly review the attractor picture proposed to underlie WM states. We then describe a general framework for a theoretical approach to learning with synapses subject to realistic constraints and outline some general requirements to be met by a mechanism of Hebbian synaptic structuring. We argue that a stochastic selection of the synapses to be updated allows for optimal memory storage, even if the number of stable synaptic states is reduced to the extreme (bistable synapses). A description follows of models of spike-driven synapses that implement the stochastic selection by exploiting the high irregularity in the pre- and post-synaptic activity. Reasons are listed why dynamic learning, that is the process by which the synaptic structure develops under the only guidance of neural activities, driven in turn by stimuli, is hard to accomplish. We provide a 'feasibility proof' of dynamic formation of WM states in this context the beneficial role of short-term depression (STD) is illustrated. by showing how an initially unstructured network autonomously develops a synaptic structure supporting simultaneously stable spontaneous and WM states in this context the beneficial role of short-term depression (STD) is illustrated. After summarizing heuristic indications emerging from the study performed, we conclude by briefly discussing open problems and critical issues still to be clarified.

Action Potentials↗

GABAergic innervation of corticotropin-releasing hormone (CRH)-secreting parvocellular neurons and its plasticity as demonstrated by quantitative immunoelectron microscopy.

GABA has been identified as an important neurotransmitter in stress-related circuitry mediating inhibitory effects on neurosecretory neurons that comprise the central limb of the hypothalamo-pituitary-adrenocortical axis. Using combinations of pre-embedding immunostaining and postembedding immunogold methods at the ultrastructural level, direct synaptic contacts were revealed between GABA-containing terminals and neurosecretory cells that were immunoreactive for corticotropin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus (PVN). The vast majority of axo-dendritic GABA synapses was symmetric (inhibitory) type, and 46% of all synaptic boutons in the medial parvocellular subdivision of the PVN were immunoreactive to GABA. Using the disector method, an unbiased stereological method on serial ultrathin sections, the total calculated number of synaptic contacts within the medial parvocellular subdivision of the PVN was 55.4 x 10(6)/mm(3). On CRH-positive profiles 20.1 x 10(6) GABAergic synaptic boutons were detected per mm(3) in control, colchicine-treated rats. In the medial parvocellular subdivision, 79% of GABAergic boutons terminated on CRH neurons. Following adrenalectomy, which increases the synthetic and secretory activities of CRH neurons, the number of GABAergic synapses that terminate on CRH-positive profiles was increased by 55%. GABA-containing boutons appeared to be swollen, while the contact surfaces of cellular membranes between GABAergic boutons and CRH-positive profiles were shorter in adrenalectomized animals than in controls. Our data provide ultrastructural evidence for direct inhibitory GABAergic control of stress-related CRH neurons and suggest a pivotal role of GABA-containing inputs in the functional plasticity of parvocellular neurosecretory neurons seen in response to adrenalectomy.

Adrenalectomy↗

Locally distributed synaptic potentiation in the hippocampus.

The long-lasting increase in synaptic strength known as long-term potentiation has been advanced as a potential physiological mechanism for many forms of both developmental and adult neuronal plasticity. In many models of plasticity, intercellular communication has been proposed to account for observations in which simultaneously active neurons are strengthened together. The data presented here indicate that long-term potentiation can be communicated between synapses on neighboring neurons by means of a diffusible messenger. This distributed potentiation provides a mechanism for the cooperative strengthening of proximal synapses and may underlie a variety of plastic processes in the nervous system.

Animals↗

Angiotensin II type-2 (AT2) receptor-mediated inhibition of NMDA receptor signalling in neuronal cells.

The N-methyl-D-aspartate (NMDA) receptor has been reported to be important in synaptic plasticity, neuronal development, normal brain function and neurologic disease. We have recently shown that PC12W cells, a subclone of rat pheochromocytoma PC12 cell line, release nitric oxide (NO), as measured by in vitro spin-trapping combined with electron paramagnetic resonance (EPR) spectroscopy, when challenged with NMDA [Norby, S.W., Weyhenmeyer, J.A. and Clarkson, R.B., Stimulation and inhibition of NO production in macrophages and neuronal cells as observed by spin trapping, Free Rad. Biol. Med., 22 (1997) 1-9]. In the present study, we provide immunochemical evidence for the expression of both the NMDAR1 and NMDAR2A/B receptor subunits in PC12W cells, that express only the angiotensin type-2 (AT2) receptor subtype, and in NG108-15 (NG108) cells, a murine neuroblastoma x glioma hybrid that expresses both the angiotensin type-1 (AT1) and AT2 receptor subtypes. We also show that treatment of PC12W cells with angiotensin (Ang II) decreases NMDA-induced NO release by 28.0 +/- 4.2%, and that this response can be attenuated by pre-treating the cells with the isoform-specific AT2 antagonist, PD 123319. Interestingly, there was no effect on cGMP accumulation in PC12W cells treated with NMDA. Similar experiments were carried out using NG108 cells since the binding properties and functional characteristics of their NMDA receptors have been previously described [Ohkuma, S., Katsura, M., Chen, D., Chen, S. and Kuriyama, K., Presence of N-methyl-D-aspartate (NMDA) receptors in neuroblastoma x glioma hybrid NG 108-15 cells-analysis using 45Ca2+ influx and [3H]MK-801 binding as functional measures, Mol. Brain Res. 22 (1994) 166-172]. Our results show that NG108 cells significantly increase cGMP levels when challenged with NMDA (21.2 +/- 5.0% over control levels), and that this response can be attenuated by the addition of angiotensin (57.1 +/- 6.2% of stimulated levels). The effect of angiotensin on NMDA-mediated changes in cGMP levels was blocked by the AT2 antagonist, PD 123319, but was not significantly changed by the addition of the AT1 antagonist, losartan. Further, Ang II action on NMDA signalling in NG108 cells was completely inhibited by the addition of both the AT1 and AT2 antagonists. Taken together, these results suggest that AngII inhibits NMDA-mediated NO and cGMP production through a mechanism involving the AT2 receptor subtype.

Animals↗

Activation of cyclin-dependent kinase 5 (Cdk5) in primary sensory and dorsal horn neurons by peripheral inflammation contributes to heat hyperalgesia.

Cyclin-dependent kinase 5 (Cdk5) is a unique member of the CDK family. It is predominantly expressed in postmitotic neurons and has been implicated in neuronal plasticity. The present study showed that Cdk5 and p35 were expressed in primary sensory and dorsal horn neurons, while p25, an N-terminal truncated derivative of p35, could only be detected in the dorsal horn neurons. Importantly, in the case of control rats, the p35 protein level was much higher in small- and medium-diameter DRG neurons than it was in large neurons. Following CFA injection, Cdk5 activity was upregulated in both primary sensory and dorsal horn neurons. Cdk5 activation in DRG neurons required p35, whereas p25 was required in the dorsal horn. Intrathecal pretreatment with Roscovitine, a specific inhibitor of Cdk5 activity, and intrathecal delivery of the DN-Cdk5(N144) gene both alleviated CFA-induced heat hyperalgesia but not mechanical allodynia. In contrast, overexpression of Cdk5, p35 or p25 in primary sensory and dorsal horn neurons significantly enhanced heat hyperalgesia. We conclude that Cdk5/p35 and Cdk5/p25 complexes in primary sensory and dorsal horn neurons may potentially be involved in nociceptive transmission after inflammation and may be employed in synaptic plasticity underlying pain hypersensitization.

Animals↗

Cumulative activation of akt and consequent inhibition of glycogen synthase kinase-3 by brain-derived neurotrophic factor and insulin-like growth factor-1 in cultured hippocampal neurons.

Brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1) seem to play key roles in mediating neuronal plasticity in the hippocampus. In the current studies, we have used cultured hippocampal neurons to study possible interactions between the two growth factors in modulating neuronal signaling pathways. BDNF and IGF-1 were found to each effectively activate the neuroprotective Akt pathway, with the magnitude of activation being at least additive when cultures were simultaneously treated with supramaximal concentrations of peptides. Likewise, a cumulative inhibitory Akt-dependent phosphorylation of proapoptotic glycogen synthase kinase-3 was observed. Immunofluorescent studies demonstrated that a single population of neurons responded to BDNF and IGF-1. In contrast, the magnitude of BDNF-stimulated extracellular signal-regulated kinase (ERK) activation was found to be much greater than that of IGF-1-stimulated ERK, such that the difference in magnitude stimulated by BDNF in the presence and absence of IGF-1 did not reach statistical significance. Consistent with the observed agonist-stimulated activation of Akt, BDNF and IGF-1 were both found to act as neurotrophins, enhancing neuronal survival under low-insulin culture conditions. Maximal survival was achieved when both growth factors were present. These findings provide insight into the significance of multiple growth factors stimulating activation of ERK and Akt in the central nervous system. In some cases, the magnitude of activation required to elicit biological responses may be achieved only with a combination of compounds.

Animals↗

Ubiquitous molecular substrates for associative learning and activity-dependent neuronal facilitation.

Recent evidence suggests that many of the molecular cascades and substrates that contribute to learning-related forms of neuronal plasticity may be conserved across ostensibly disparate model systems. Notably, the facilitation of neuronal excitability and synaptic transmission that contribute to associative learning in Aplysia and Hermissenda, as well as associative LTP in hippocampal CA1 cells, all require (or are enhanced by) the convergence of a transient elevation in intracellular Ca2+ with transmitter binding to metabotropic cell-surface receptors. This temporal convergence of Ca2+ and G-protein-stimulated second-messenger cascades synergistically stimulates several classes of serine/threonine protein kinases, which in turn modulate receptor function or cell excitability through the phosphorylation of ion channels. We present a summary of the biophysical and molecular constituents of neuronal and synaptic facilitation in each of these three model systems. Although specific components of the underlying molecular cascades differ across these three systems, fundamental aspects of these cascades are widely conserved, leading to the conclusion that the conceptual semblance of these superficially disparate systems is far greater than is generally acknowledged. We suggest that the elucidation of mechanistic similarities between different systems will ultimately fulfill the goal of the model systems approach, that is, the description of critical and ubiquitous features of neuronal and synaptic events that contribute to memory induction.

Animals↗

Neurolipidomics: challenges and developments.

The field of lipidomics is one of the most rapidly expanding areas of systems biology research. Considering the uniqueness and complexity of the lipidome in the nervous system (i.e., neurolipidome), neurolipidomics remains quite challenging but exciting. With the recent development of mass spectrometry (MS)-based lipidomics, particularly the rapid improvement of multi-dimensional MS-based shotgun lipidomics, much progress has been made in neurolipidomics. As the accelerated development of future technologies enables lipidomics penetrance into lower and lower abundance regions of mass contents of individual lipid molecular species, it can be anticipated that many biochemical mechanisms underlying lipid metabolism critical to neuronal disease states will be increasingly uncovered. Through exploiting the information content inherent in the complexity of neuronal lipid composition and kinetic turnover which can be revealed by neurolipidomics, substantial insights into neuronal plasticity and gene function can be gathered. Through neurolipidomics, the markers for these neuronal diseases which identify pathological alterations and are diagnostic of disease onset, progression or severity may potentially be discovered. Accordingly, with neurolipidomics, our understanding of the complexities of the nervous system will be undoubtedly accelerated, as many mysteries are resolved.

Animals↗

Plasticity of dendritic spine formation: a state-dependent stochastic process.

This study proposes that plasticity of dendritic spine formation may be modeled as distribution patterns imbedded in a spine length-dependent and density-dependent stochastic process. Modeling the jewel fish tectal interneuron revealed a critical 10-36 micron region where spine length plasticity was predicted to be most detectable. This hypothesis was tested by comparing neurons sampled from jewel fish reared for 4 years in a crowded environment (1 fish/5.64 l) with uncrowded controls (1 fish/25 l). The interaction between fish groups and the location of spine length differences was significant (p less than 0.01) within the basal 10-30 micron dendritic segment. Spine head widths were also significantly smaller (p less than 0.01) in the crowded fish over the entire dendrite. These findings suggest two modes of neuronal plasticity: (1) plasticity of spine length during formation, and (2) plasticity in spine head width after the spine is formed.

Animals↗

Growth factor modulation of substrate-specific morphological patterns in Aplysia bag cell neurons.

Components of the extracellular matrix (ECM) can act not only as passive substrates for neuronal attachment and outgrowth but also as active sites for signal transduction. Thus, specific ECM components may modulate effects of growth factors (GFs) that play an important role in structural changes in development and adult neuronal plasticity. In this study we examined the interaction of cultured Aplysia bag cell neurons (BCNs) with components of ECM and different GFs. Different ECM substrata induce a substrate-specific BCN morphology: BCNs grown on collagen or poly-L-lysine have larger soma diameter and more extensive neurite outgrowth than BCNs grown on laminin or fibronectin. BCNs also interact in a substrate-dependent way with GFs: BDNF treatment leads to a reduction of outgrowth on poly-L-lysine but an enhancement on fibronectin and laminin. CNTF reduces the soma diameter on collagen IV but enlarges it on laminin or fibronectin. In contrast, NGF induces a reduction of both soma diameter and outgrowth, on all substrata. Plating of BCNs in the presence of anti-beta1-integrin reduces adhesion to fibronectin but does not change outgrowth. In contrast, RGD peptides block adhesion to laminin and poly-L-lysine and, additionally, reduce outgrowth on laminin. These data suggest that BCNs use different beta1-integrin-dependent as well as RGD-dependent mechanisms for adhesion and outgrowth on different ECM substrata, providing possible sites of modulation by specific GFs.

Animals↗

Neural plasticity: Part 3. Responses to lesions in the peripheral nervous system.

This paper describes some of the remarkable recuperative responses that neurons of the peripheral nervous system have to injury of their axons. The initial response is a sealing of the cut ends of the axons, followed by orderly degenerative and phagocytic events in the segments lying distal and proximal to the lesion. The chromatolytic changes occurring in the cell body are adaptive responses involving the morphological, physiological, and biochemical properties of the neuron. The cell loses dendrites and synapses, its electrophysiological properties are altered, and its biochemistry is altered to prepare the neuron for synthesizing proteins needed for formation of growth cones and regeneration of the axon. During this period, the denervated muscle undergoes dramatic atrophic changes that not only modify the electrical nd chemical properties of its membrane but also reduce the diameter and weight of its fibers. This denervation atrophy of muscle is reversible if reinnervation occurs before muscle material has been replaced by connective tissue. Responses to injury of sensory axons depend on the site of the lesion. Cutting a dorsal root causes Wallerian degeneration of the primary afferents' central processes. Collateral sprouts from neighboring uncut root fibers are thought to take over the vacant synapses on the second-order neurons in the dorsal horn. Cutting a sensory axon peripherally eliminates the receptive field of the primary afferent initially, but in time, collaterals from neighboring skin afferents provide the second-order neurons with a new receptive field. Synaptic reclamation and receptive field reorganization are but two dramatic examples of neuronal plasticity that lead to "rewired" neural circuitry.

Atrophy↗

Distribution and possible roles of the highly polysialylated neural cell adhesion molecule (NCAM-H) in the developing and adult central nervous system.

The neural cell adhesion molecule (NCAM) is a cell surface glycoprotein which is thought to mediate cell adhesion and recognition. During developmental stages, NCAM is highly polysialylated (NCAM-H) by a unique alpha-2,8-linked polysialic acid chain (PSA), and this PSA portion of NCAM-H has been found to be closely associated with various developmental processes of the nervous system. Further, recent immunohistochemical investigations have revealed that even in the adult nervous system, a persistent PSA expression has been found confined to several regions: the olfactory bulb, the piriform cortex, the hippocampal dentate gyrus, the hypothalamus, some nuclei of the medulla and the dorsal horn of the spinal cord, which are related directly or indirectly to sensory systems. Moreover, in the dentate gyrus and olfactory bulb the expression is connected with adult neurogenesis that may add new neuronal circuits to the adult neural tissue. Therefore, the possible role of NCAM-H in the central nervous system may be associated not only with neural development, but also with adult functions, such as the processing system of sensory information and neuronal plasticity.

Animals↗

Kindling stimulation induces c-fos protein(s) in granule cells of the rat dentate gyrus.

Alterations in neuronal gene expression have been proposed to account for permanent changes in brain function such as learning and memory. In particular, it has been suggested that protooncogenes such as c-fos may be rapidly induced in conditions that lead to neuronal plasticity and evoke permanent changes in the expression of effector genes. Concentrations of the c-fos proto-oncogene increase rapidly following depolarization-induced calcium influx in non-dividing neuronally differentiated PC 12 cells. Recently, the presence and induction of c-fos in the adult brain and spinal cord has been observed. Here we report that electrically-induced seizure activity, which leads to a permanent increase in the response of the brain to future seizures (kindling), rapidly and transiently increases c-fos protein-like immunoreactivity in the nuclei of granule cells in the rat dentate gyrus. These results suggest that c-fos protein is present within the nuclei of adult mammalian neurons, and could be involved in plastic changes in the nervous system associated with seizure activity.

Animals↗

Carbamazepine protects against megencephaly and abnormal expression of BDNF and Nogo signaling components in the mceph/mceph mouse.

Carbamazepine (CBZ) is a commonly used antiepileptic drug known to block voltage-gated sodium channels. Infants exposed to CBZ in utero show reduced head circumference, for reasons unknown. We investigated CBZ's effect on neural growth in megencephaly (mceph/mceph) mice lacking functional Kv1.1. Mice fed with CBZ were assessed for brain structure size, seizure behavior and expression of markers for neuronal plasticity and rescue in brain. CBZ counteracted brain overgrowth and the increased size of neurons in the mceph/mceph mouse. These effects of CBZ occurred at doses that did not fully suppress epileptic behavior. Furthermore, CBZ normalized Bdnf mRNA levels and mRNA species encoding Nogo signaling pathway proteins. In conclusion, CBZ protects efficiently against abnormal growth and abnormal expression patterns of nerve growth signaling systems in the mceph/mceph brain. These observations and the effect of CBZ in utero suggest that CBZ treatment might be advantageous in some types of human idiopathic megalencephaly.

Animals↗

Strain-dependent recovery of spontaneous hindlimb movement in spinal cord transected mice (CD1, C57BL/6, BALB/c).

Reorganization and plasticity after spinal cord injury have been recently shown to take place in sublesional neuronal networks, but the possibility of strain-dependent changes at that level has never been explored. The authors studied the spontaneous return of hindlimb movement in low-thoracic spinal cord transected (Tx) mice from 3 commonly used strains. Without intervention, most CD1, C57BL/6, and BALB/c mice displayed some hindlimb movement recovery after Tx. Although all assessment methods unanimously reported that CD1 displayed higher recovery levels than did the C57BL/6 and BALB/c, higher scores were generally found with the Antri-Orsal-Barthe (M. Antri, D. Orsal, & J. Y. Barthe, 2002) and the Average Combined Score (P. A. Guertin, 2005a) methods. Such spontaneous recovery in low-thoracic Tx mice is likely the result of neuronal plasticity at the lumbosacral spinal cord level, suggesting that these sublesional changes are strain dependent.

Animals↗

Multiple spatiotemporal modes of actin reorganization by NMDA receptors and voltage-gated Ca2+ channels.

Cytoskeleton is believed to contribute to activity-dependent processes underlying neuronal plasticity, such as regulations of cellular morphology and localization of signaling proteins. However, how neuronal activity controls actin cytoskeleton remains obscure. Taking advantage of confocal imaging of enhanced GFP-actin in the primary culture of hippocampal neurons, we show that synaptic activity induces multiple types of actin reorganization, both at the spines and at the somatic periphery. Activation of N-methyl-d-aspartate receptors, accompanied with a local rise in [Ca(2+)]i, was sufficient to trigger a slow and sustained recruitment of actin into dendritic spines. In contrast, opening of voltage-gated Ca(2+) channels rapidly and reversibly enhanced cortical actin at the somatic periphery but not in the spines, in keeping with a high transient rise in somatic [Ca(2+)]i. These data suggest that spatiotemporal dynamics of [Ca(2+)]i, triggered by activation of N-methyl-d-aspartate receptors and voltage-gated Ca(2+) channels, provides the molecular basis for activity-dependent actin remodeling.

Actins↗

Glucocorticoid exposure at the dose used clinically alters cytoskeletal proteins and presynaptic terminals in the fetal baboon brain.

Glucocorticoids have been used for 30 years to accelerate fetal lung maturation in human pregnancy at risk of preterm delivery. Exposure to inappropriate levels of steroid, however, leads to altered maturation of the cardiovascular, metabolic and central nervous systems. The effects of betamethasone on neuronal development and function were determined in the fetal baboon brain by examination of cytoskeletal microtubule associated proteins (MAPs) and the presynaptic marker protein synaptophysin. At 0.73 gestation, commencing 28 weeks of gestation, pregnant baboons received four doses of saline (n = 8) or 87.5 microg (kg body weight)(-1) betamethasone I.M. (n = 7) 12 h apart. This dose is equivalent to 12 mg betamethasone administered daily over two consecutive days to a 70 kg woman. Baboons underwent Caesarean section 12 h after the last injection. Paraffin sections of the fetal neocortex and the underlying white matter were labelled immunohistochemically against MAP1B, MAP2abc, MAP2ab and synaptophysin and stained histochemically with hematoxylin-eosin and silver. Tissue staining was quantified morphometrically. Betamethasone exposure resulted in decreased immunoreactivity (IR) of MAP1B by 34.3 % and MAP2abc by 34.1 % (P < 0.05). Loss of MAP2 IR was due to loss of IR of the juvenile isoform MAP2c (P < 0.05). MAP1B and MAP2c are involved in neuritogenesis and neuronal plasticity. Synaptophysin IR was reduced by 51.8 % (P < 0.01). These changes might reflect functional neuronal disturbances because they were not accompanied by an alteration of the density of neurofibrils or neuronal necrosis. These results are in agreement with earlier findings of alterations of cytoskeletal proteins and presynaptic terminals in the fetal sheep brain after betamethasone infusion directly to the fetus and support a common effect of inappropriate fetal exposure to glucocorticoids on neuronal cytoskeleton and synapses in mammalian species.

Animals↗

A unifying hypothesis of Alzheimer's disease. IV. Causation and sequence of events.

Contrary to common concepts, the brain in Alzheimer's disease (AD) does not follow a suicide but a rescue program. Widely shared features of metabolism in starvation, hibernation and various conditions of energy deprivation, e.g. ischemia, allow the definition of a deprivation syndrome which is a phylogenetically conserved adaptive response to energetic stress. It is characterized by hypometabolism, oxidative stress and adjustments of the glucose-fatty acid cycle. Cumulative evidence suggests that the brain in aging and AD actively adapts to the progressive fuel deprivation. The counterregulatory mechanisms aim to preserve glucose for anabolic needs and promote the oxidative utilization of ketone bodies. The agent mediating the metabolic switch is soluble Abeta which inhibits glucose utilization and stimulates ketone body utilization at various levels. These processes, which are initiated during normal aging, include inhibition of pro-glycolytic neurohormones, cholinergic transmission, and pyruvate dehydrogenase, the key transmitter and effector systems regulating glucose metabolism. Hormonal and effector systems which promote ketone body utilization, such as glucocorticosteroid and galanin activity, GABAergic transmission, nitric oxide, lipid transport, Ca2+ elevation, and ketone body metabolizing enzymes, are enhanced. A multitude of risk factors feed into this pathophysiological cascade at a variety of levels. Taking into account its pleiotropic regulatory actions in the deprivation response, a new name for Abeta is suggested: deprivin. On the other hand, cumulative evidence, taken together compelling, suggests that senile plaques are the dump rather than the driving force of AD. Moreover, the neurotoxic action of fibrillar Abeta is a likely in vitro artifact but does not contribute significantly to the in vivo pathophysiological events. This archaic program, conserved from bacteria to man, aims to ensure the survival of a deprived organism and controls such divergent processes as sporulation, hibernation, aging and aging-related diseases. In contrast to the immature brain, ketone body utilization of the aged brain is no longer sufficient to meet the energetic demands and is later supplemented by lactate, thus recapitulating in reverse order the sequential fuel utilization of the immature brain. The transduction pathways which operate to switch metabolism also convey the programming and balancing of the de-/redifferentiation/apoptosis cell cycle decisions. This encompasses the reiteration of developmental processes such as transcription factor activation, tau hyperphosphorylation, and establishment of growth factor independence by means of Ca2+ set point shift. Thus, the increasing energetic insufficiency results in the progressive centralization of metabolic activity to the neuronal soma, leading to pruning of the axonal/dendritic trees, loss of neuronal polarity, downregulation of neuronal plasticity and, eventually, depending on the Ca2+ -energy-redox homeostasis, degeneration of vulnerable neurons. Finally, it is outlined that genetic (e.g. Down's syndrome, APP and presenilin mutations and apoE4) and environmental risk factors represent progeroid factors which accelerate the aging process and precipitate the manifestation of AD as a progeroid systemic disease. Aging and AD are related to each other by threshold phenomena, corresponding to stage 2, the stage of resistance, and stage 3, exhaustion, of a metabolic stress response.

Acetylcholine↗