Responses of cutaneous mechanoreceptors within fingerpad to stimulus information for tactile softness sensation of materials

Softness sensation is one of primitive tactile textures. While the psychophysical characteristics of softness sensation have been thoroughly studied, it is lack of a deep understanding of the underlying neuromechanical principles. On the stimulus–response processes of human fingerpad touching fabrics and the physiological properties of slowly adapting type I (SAIs) cutaneous mechanoreceptors within fingerpad, a fabric-skin-receptor coupling model was built and validated. By the fabric-skin-receptor model a series of numerical experiments was conducted, and how the evoked neural responses of cutaneous mechanoreceptors change with the composite compliance of both fingerpad skin and the materials in contact was investigated. The results indicated that the evoked neural responses of populations of cutaneous mechanoreceptors by the physical stimulus from fabrics were nearly proportional to the perceived softness magnitude, and nonlinearly increased and then decreased with the effective elastic modulus of fabrics or the relative elastic modulus of fabrics to soft tissues within fingerpad, where the nonlinear inflection point depended on the touching force level. Therefore, it concluded that the tactile judgment of the physical information for softness sensation of objects was an encoding of neural responses of populations of SAIs cutaneous mechanoreceptors, and the physical information depended on the mechanical interaction of fingerpad and objects in contact.     

Intracellular Signaling in Primary Sensory Neurons and Persistent Pain

During evolution, living organisms develop a specialized apparatus called nociceptors to sense their environment and avoid hazardous situations. Intense stimulation of high threshold C- and Aδ-fibers of nociceptive primary sensory neurons will elicit pain, which is acute and protective under normal conditions. A further evolution of the early pain system results in the development of nociceptor sensitization under injury or disease conditions, leading to enhanced pain states. This sensitization in the peripheral nervous system is also called peripheral sensitization, as compared to its counterpart, central sensitization. Inflammatory mediators such as proinflammatory cytokines (TNF-α, IL-1β), PGE₂, bradykinin, and NGF increase the sensitivity and excitability of nociceptors by enhancing the activity of pronociceptive receptors and ion channels (e.g., TRPV1 and Na_v1.8). We will review the evidence demonstrating that activation of multiple intracellular signal pathways such as MAPK pathways in primary sensory neurons results in the induction and maintenance of peripheral sensitization and produces persistent pain. Targeting the critical signaling pathways in the periphery will tackle pain at the source. Special issue article in honor of Dr. Ji-Sheng Han.     

Psychophysical and neurobiological evidence that the oral sensation elicited by carbonated water is of chemogenic origin

The sensation produced by carbonated beverages has been attributed to chemical excitation of nociceptors in the oral cavity via the conversion of CO(2) to carbonic acid in a reaction catalyzed by carbonic anhydrase. In separate studies, we tested if the carbonic anyhdrase blocker, acetazolamide, reduced either the intensity of sensation in humans or c-fos expression by trigeminal neurons in rats, evoked by application of carbonated water to the tongue. In the psychophysical experiment, one-half of the dorsal tongue was pretreated with acetazolamide (1 or 2%), after which the tongue was exposed bilaterally to carbonated water. In a two-alternative forced-choice paradigm, subjects chose which side of the tongue yielded a stronger sensation and additionally rated the magnitude of sensation on each side. Pretreatment with acetazolamide reduced the magnitude of sensation elicited by carbonated water in a concentration-dependent manner, since a significant majority of subjects chose the untreated side of the tongue as having a stronger sensation and assigned significantly higher intensity ratings to that side. Acetazolamide did not affect the irritant sensation from citric acid, while capsaicin pretreatment reduced both the sensation elicited by carbonated water and the irritation induced by citric acid application. In a separate experiment using rats, delivery of carbonated water to the tongue significantly increased the number of cells expressing c-fos-like immunoreactivity in the dorsomedial trigeminal nucleus caudalis (versus saline controls); this was significantly reduced by pretreatment with acetazolamide. Our results support the hypothesis that carbonated water activates lingual nociceptors via conversion of CO(2) to carbonic acid; the nociceptors in turn excite trigeminal neurons involved in signaling oral irritation.     

Inhibition of Inactive States of Tetrodotoxin-Sensitive Sodium Channels Reduces Spontaneous Firing of C-Fiber Nociceptors and Produces Analgesia in Formalin and Complete Freund’s Adjuvant Models of Pain

While genetic evidence shows that the Nav1.7 voltage-gated sodium ion channel is a key regulator of pain, it is unclear exactly how Nav1.7 governs neuronal firing and what biophysical, physiological, and distribution properties of a pharmacological Nav1.7 inhibitor are required to produce analgesia. Here we characterize a series of aminotriazine inhibitors of Nav1.7 in vitro and in rodent models of pain and test the effects of the previously reported “compound 52” aminotriazine inhibitor on the spiking properties of nociceptors in vivo. Multiple aminotriazines, including some with low terminal brain to plasma concentration ratios, showed analgesic efficacy in the formalin model of pain. Effective concentrations were consistent with the in vitro potency as measured on partially-inactivated Nav1.7 but were far below concentrations required to inhibit non-inactivated Nav1.7. Compound 52 also reversed thermal hyperalgesia in the complete Freund’s adjuvant (CFA) model of pain. To study neuronal mechanisms, electrophysiological recordings were made in vivo from single nociceptive fibers from the rat tibial nerve one day after CFA injection. Compound 52 reduced the spontaneous firing of C-fiber nociceptors from approximately 0.7 Hz to 0.2 Hz and decreased the number of action potentials evoked by suprathreshold tactile and heat stimuli. It did not, however, appreciably alter the C-fiber thresholds for response to tactile or thermal stimuli. Surprisingly, compound 52 did not affect spontaneous activity or evoked responses of Aδ-fiber nociceptors. Results suggest that inhibition of inactivated states of TTX-S channels, mostly likely Nav1.7, in the peripheral nervous system produces analgesia by regulating the spontaneous discharge of C-fiber nociceptors.     

Fingerprint lines may not directly affect SA-I mechanoreceptor response

Understanding how skin microstructure affects slowly adapting type I (SA-I) mechanoreceptors in encoding edge discontinuities is fundamental to understanding our sense of touch. Skin microstructure, in particular papillary ridges, has been thought to contribute to edge and gap sensation. Cauna's 1954 model of touch sensibility describes a functional relationship between papillary ridges and edge sensation. His lever arm model proposes that the papillary ridge (exterior fingerprint line) and underlying intermediate ridge operate as a single unit, with the intermediate ridge acting as a lever which magnifies indentation imposed at the papillary ridge. This paper contests the validity of the lever arm model. While correctly representing the anatomy, this mechanism inaccurately characterizes the function of the papillary ridges. Finite element analysis and assessment of the critical anatomy indicate that papillary ridges have little direct effect on how SA-I receptors respond to the indentation of static edges. Our analysis supports a revised (stiff shell-elastic bending support) interpretation where the epidermis is split into two major layers with a stiff, deformable shell over an elastic bending support. Recent physiological, electrophysiological, and psychophysical findings support our conclusion that the function of the intermediate ridge is distinct from the function of the papillary ridge.     

Somatosensory afferent inputs release 5-HT and NA from the spinal cord

Endogenous serotonin (5-HT) and noradrenaline (NA) release by somatosensory afferent inputs was investigated at the level of the spinal cord using in vivo microdialysis technique combined with high performance liquid chromatography and electrochemical detection (HPLC-ECD). Selective stimulation of large myelinated Aβ afferent fibers significantly increased 5-HT release to 151.1 ±10.1% of the control, but did not affect NA release. However, selective stimulation of small myelinated Aδ fibers released NA rather than 5-HT. The NA level enhanced to 128.8±6.4% of the control after Aδ fibers were stimulated with the intensity of 6 times threshold. Stimulation of unmyelinated C fibers unavoidably excited the Aβ and Aδ afferent fibers, causing both 5-HT and NA release from the spinal cord. The results suggest that both innocuous and noxious information may activate serotonergic descending pathways. The noradrenergic descending pathways are only triggered by noxious inputs transmitted by small afferent fibers.     

Compensatory mechanisms to heal neuroplasticity impairment under Alzheiemr’s disease neurodegeneration. I: The role of amyloid beta and its’ precursor protein

In-depth scholar literature analysis of Alzheimer’s disease neurodegenerative features of amyloid beta protein neurochemistry modification and excessive phosphorylation of tau protein (and associated neuronal cytoskeleton rearrangements) are secondary phenomena. At early disease stage these neurobiochemical mechanisms are reversible and serve to heal an impairment of biophysical properties of neuronal membranes, neurotransmission, basic neuronal function and neuroplasticity, while preserving anatomical and functional brain fields. Aβ and tau could well serve to biochemically restore physico-chemical properties of neual membranes due to a role these proteins play in lipid metabolism. Under such scenario therapeutic block of aggregation and plaque formation of Aβ and inhibition of tau phosphorylation, as well as pharmaceutical modification of other secondary neurodegenerative features (such as a cascade of oxidative stress reactions) are unable to provide an effective cure of Alzheimer’s disease and related pathologies of the Central and peripheral nervous systems, because they are not arraying primary pathagenetic cause. We review the role of Aβ in compensatory mechanisms of neuroplasticity restoration under normal physiological condition and Alzheimer’s disease.     

Aβ Toxicity in Alzheimer's Disease

Alzheimer's Disease (AD), the most common age-related neurodegenerative disorder, is characterized by progressive cognitive decline, synaptic loss, the formation of extracellular β-amyloid plaques and intracellular neurofibrillary tangles, and neuronal cell death. Despite the massive neuronal loss in the ‘late stage’ of disease, dendritic spine loss represents the best pathological correlate to the cognitive impairment in AD patients. The ‘amyloid hypothesis’ of AD recognizes the Aβ peptide as the principal player in the pathological process. Many lines of evidence point out to the neurotoxicity of Aβ, highlighting the correlation between soluble Aβ oligomer accumulation, rather than insoluble Aβ fibrils and disease progression. Pathological increase of Aβ in AD brains, resulting from an imbalance between its production, aggregation and clearance, might target mitochondrial function promoting a progressive synaptic impairment. The knowledge of the exact mechanisms by which Aβ peptide impairs neuronal function will help us to design new pharmacological tools for preventing AD neurodegeneration.     

The influence of topical capsaicin on the local thermal control of skin blood flow in humans

To test whether heat-sensitive receptors participate in the cutaneous vascular responses to direct heating, we monitored skin blood flow (SkBF; laser Doppler flowmetry) where the sensation of heat was induced either by local warming (T(Loc); Peltier cooling/heating unit) or by both direct warming and chemical stimulation of heat-sensitive nociceptors (capsaicin). In part I, topical capsaicin (0.075 or 0.025%) was applied to 12 cm(2) of skin 1 h before stepwise local warming of untreated and capsaicin-treated forearm skin. Pretreatment with 0.075% capsaicin cream shifted the SkBF/T(Loc) relationship to lower temperatures by an average of 6 +/- 0.8 degrees C (P < 0.05). In part II, we used a combination of topical capsaicin (0.025%) and local warming to evoke thermal sensation at one site and only local warming to evoke thermal sensation at a separate site. Cutaneous vasomotor responses were compared when the temperatures at these two sites were perceived to be the same. SkBF differed significantly between capsaicin and control sites when compared on the basis of actual temperatures, but that difference became insignificant when compared on the basis of the perceived temperatures. These data suggest heat-sensitive nociceptors are important in the cutaneous vasodilator response to local skin warming.     

Beta-amyloid induced changes in A-type K<Superscript>+</Superscript> current can alter hippocampo-septal network dynamics

Alzheimer’s disease (AD) progression is usually associated with memory deficits and cognitive decline. A hallmark of AD is the accumulation of beta-amyloid (Aβ) peptide, which is known to affect the hippocampal pyramidal neurons in the early stage of AD. Previous studies have shown that Aβ can block A-type K⁺ currents in the hippocampal pyramidal neurons and enhance the neuronal excitability. However, the mechanisms underlying such changes and the effects of the hyper-excited pyramidal neurons on the hippocampo-septal network dynamics are still to be investigated. In this paper, Aβ-blocked A-type current is simulated, and the resulting neuronal and network dynamical changes are evaluated in terms of the theta band power. The simulation results demonstrate an initial slight but significant theta band power increase as the A-type current starts to decrease. However, the theta band power eventually decreases as the A-type current is further decreased. Our analysis demonstrates that Aβ blocked A-type currents can increase the pyramidal neuronal excitability by preventing the emergence of a steady state. The increased theta band power is due to more pyramidal neurons recruited into spiking mode during the peak of pyramidal theta oscillations. However, the decreased theta band power is caused by the spiking phase relationship between different neuronal populations, which is critical for theta oscillation, is violated by the hyper-excited pyramidal neurons. Our findings could provide potential implications on some AD symptoms, such as memory deficits and AD caused epilepsy.     

Frequency resolution and spectral integration (critical band analysis) in single units of the cat primary auditory cortex

Frequency resolution and spectral filtering in the cat primary auditory cortex (AI) were mapped by extracellular recordings of tone responses in white noise of various bandwidths. Single-tone excitatory tuning curves, critical bandwidths, and critical ratios were determined as a function of neuronal characteristic frequency and tone level. Single-tone excitatory tuning curves are inadequate measures of frequency resolution and spectral filtering in the AI, because their shapes (in most neurons) deviated substantially from the shapes of “tuning curves for complex sound analysis”, the curves determined by the band limits of the critical bandwidths. Perceptual characteristics of spectral filtering (intensity independence and frequency dependence) were found in average critical bandwidths of neurons from the central and ventral AI. The highest frequency resolution (smallest critical bandwidths) reached by neurons in the central and ventral AI equaled the psychophysical frequency resolution. The dorsal AI is special, since most neurons there had response properties incompatible with psychophysical features of frequency resolution. Perceptual characteristics of critical ratios were not found in the average neuronal responses in any area of the AI. It seems that spectral integration in the way proposed to be the basis for the perception of tones in noise is not present at the level of the AI. Accepted: 21 July 1997     

Cryptotanshinione Inhibits β-Amyloid Aggregation and Protects Damage from β-Amyloid in SH-SY5Y Cells

The deposition of amyloid β-protein (Aβ) fibrils into plaques within the brain parenchyma and along cerebral blood vessels is a hallmark of Alzheimer’s disease (AD). Aβ42 oligomers and fibrils cause the breakdown of neural circuits, neuronal death and eventually dementia. Drugs that inhibit Aβ42 aggregation may be a novel direction in AD drug discovery. Cryptotanshinone (CTS), an active component of the medicinal herb Salvia miltiorrhiza, has been shown to improve learning and memory in several pharmacological models of AD. However, the effects of CTS on the Aβ aggregation and toxicity are unclear. The current work shows the effectiveness of CTS on the inhibition of Aβ42 aggregation and toxicity to human neuroblastoma cells. In this study, we demonstrated that CTS can inhibit Aβ42 spontaneous aggregation using thioflavin T fluorescence assay and transmission electron microscopy. Furthermore, we investigated the effects of CTS on Aβ-induced oxidative cell death in cultured SH-SY5Y cells. MTT and lactate dehydrogenase assays showed that CTS reduced the cytotoxicity induced by Aβ42. CTS also dramatically reduced Aβ42-induced cellular apoptosis and increased level of reactive oxygen species in these cells. Our study suggests that CTS may be useful in the inhibition or prevention of AD development and progression.     

A theory for the use of visual orientation information which exploits the columnar structure of striate cortex

A neural model is constructed based on the structure of a visual orientation hypercolumn in mammalian striate cortex. It is then assumed that the perceived orientation of visual contours is determined by the pattern of neuronal activity across orientation columns. Using statistical estimation theory, limits on the precision of orientation estimation and discrimination are calculated. These limits are functions of single unit response properties such as orientation tuning width, response amplitude and response variability, as well as the degree of organization in the neural network. It is shown that a network of modest size, consisting of broadly orientation selective units, can reliably discriminate orientation with a precision equivalent to human performance. Of the various network parameters, the discrimination threshold depends most critically on the number of cells in the hypercolumn. The form of the dependence on cell number correctly predicts the results of psychophysical studies of orientation discrimination. The model system's performance is also consistent with psychophysical data in two situations in which human performance is not optimal. First, interference with orientation discrimination occurs when multiple stimuli activate cells in the same hypercolumn. Second, systematic errors in the estimation of orientation can occur when a stimulus is composed of intersecting lines. The results demonstrate that it is possible to relate neural activity to visual performance by an examination of the pattern of activity across orientation columns. This provides support for the hypothesis that perceived orientation is determined by the distributed pattern of neural activity. The results also encourage the view of neural activity. The results also are determined by the responses of many neurons rather than the sensitivity of individual cells.     

Role of Cyclin-Dependent Kinase 5 in the Neurodegenerative Process Triggered by Amyloid-Beta and Prion Peptides: Implications for Alzheimer’s Disease and Prion-Related Encephalopathies

Tau hyperphosphorylation, amyloid plaques, and neuronal death are major neuropathological features of Alzheimer’s disease (AD) and Prion-related encephalopathies (PRE). Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase, active in post-mitotic neurons, where it regulates survival and death pathways. Overactivation of Cdk5 is conferred by p25, a truncated fragment of the p35 activator formed upon calpain activation. Cdk5 deregulation causes abnormal phosphorylation of microtubule-associated protein tau, leading to neurodegeneration. In this work we investigated the involvement of Cdk5 in the neurodegeneration triggered by amyloid-beta (Aβ) and prion (PrP) peptides, the culprit agents of AD and PRE. As a work model, we used cultured rat cortical neurons treated with Aβ_1–40 and PrP_106–126 synthetic peptides. The obtained data show that apoptotic neuronal death caused by both the peptides was in part due to Cdk5 deregulation. After peptide treatment, p25 levels were significantly enhanced in a pattern consistent with the augment in calpain activity. Moreover, Aβ_1–40 and PrP_106–126 increased the levels of tau protein phosphorylated at Ser202/Thr205. Cdk5 (roscovitine) and calpain (MDL28170) inhibitors reverted tau hyperphosphorylation and prevented neuronal death caused by Aβ_1–40 and PrP_106–126. This study demonstrates, for the first time, that Cdk5 is involved in PrP-neurotoxicity. Altogether, our data suggests that Cdk5 plays an active role in the pathogenesis of AD and PRE.     

TCRJ and BCRJ gene segments contain 5′ D-segment sequences that contribute to repertoire diversity

T cell receptor (TCR) and B cell receptors (BCR) junctions, also known as the CDR3, are where the V, D, and J gene segments converge, coding for a loop structure important for contacting ligands. J segments contribute to the formation of the CDR3 loop through their 5′ ends that vary in length and show high sequence variability. The 5′ ends of J segments of TCRα genes show nucleotide sequence similarities to TCRDδ segments as high as 89% and show a preponderance of murine TCRDδ2 or human TCRDδ3 amino acid sequence similarities. Surprisingly, most of the 5′ ends of TCRJγ segments show nucleotide and amino acid sequence similarities with TCRDβ segments. All murine and human BCRJH segments and most TCRJδ segments contain amino acid sequences at their 5′ ends that resemble their own D segments, a finding that is not seen with TCRJβ segments. TCRα and TCRγ genes thus make up for their lack of separate D segments with distinct D-like segments that are built into the 5′ ends of their J segments. Additionally, in some cases, TCR and BCR genes that utilize separate D segments also receive additional D-like contributions though the 5′ ends of their J segments to add additional diversity to their CDR3 loops.     

On the directionality of cortical interactions studied by structural analysis of electrophysiological recordings

To investigate the directionality of neural interactions as assessed by electrophysiology, we adapted methods of structural analysis from the field of econometrics. In particular, within the framework of autoregressive modelling of the data, we considered quantitative measures of linear relationship between multiple time series adopting the Wiener-Granger concept of causality. The techniques were evaluated with local field potential measurements from the cat visual system. Here, several issues had to be addressed. First, out of several statistical tests of the stationarity of local field potentials considered, those based on the Kolmogorov-Smirnov and on the reverse arrangement statistics proved to be most powerful. The application of those tests to the experimental data showed that the large part of the local field potentials can be considered stationary on a time scale of 1 s. Second, out of the several investigated methods for the determination of an optimal order of the autoregressive model, the Akaike Information Criterion had the most suitable properties. The identified order of the model, across different repetitions of the trials, was consistently 5–8. Third, although the individual segments of field potentials used for the analysis were relatively short, the methods of structural analysis applied produced reliable results, confirming findings of simulations of data with similar properties. Furthermore the features of the estimated models were consistent among trials, so that the analysis of average measures of interaction appears to be a viable approach to investigate the relationship between the recording sites. In summary, the statistical methods considered have proved to be suitable for the study of the directionality of neuronal interactions. Received: 13 August 1998 / Accepted in revised form: 19 March 1999     

Amyloid-β Decreases Nitric Oxide Production in Cultured Retinal Neurons: A Possible Mechanism for Synaptic Dysfunction in Alzheimer’s Disease?

The neurotoxicity of the amyloid-β peptide (Aβ) appears to be, at least in part, related to pathological activation of glutamate receptors by Aβ aggregates. However, the downstream signaling pathways leading to neurodegeneration are still incompletely understood. Hyperactivation of nitric oxide synthase (NOS) and increased nitric oxide (NO) production have been implicated in excitotoxic neuronal damage caused by overactivation of glutamate receptors, and it has been suggested that increased NO levels might also play a role in neurotoxicity in Alzheimer’s disease. We have examined the effect of blockade of NO production on the neurotoxicity instigated by Aβ₄₂ and by elevated concentrations of glutamate in chick embryo retinal neurons in culture. Results showed that l-nitroarginine methyl ester, a potent inhibitor of all NOS isoforms, had no protective effect against neuronal death induced by either Aβ₄₂ (20 μM) or glutamate (1 mM). Surprisingly, at short incubation times both Aβ and glutamate decreased NO production in retinal neuronal cultures in the absence of neuronal death. Thus, excitotoxic insults induced by Aβ and glutamate cause inhibition rather than activation of NO synthase in retinal neurons, suggesting that cell death induced by Aβ or glutamate is not related to increased NO production. On the other hand, considering the role of NO in long term potentiation and synaptic plasticity, the decrease in NO levels instigated by Aβ and glutamate suggests a possible mechanism leading to synaptic failure in AD.     

BDNF-, IGF-1- and GDNF-Secreting Human Neural Progenitor Cells Rescue Amyloid β-Induced Toxicity in Cultured Rat Septal Neurons

Alzheimer’s disease (AD) is characterized by the depositions of amyloid-β (Aβ) proteins, resulting in a reduction of choline acetyltransferase (ChAT) activity of AD brain in the early stages of the disease. Several growth factors, including brain-derived neurotrophic factor (BDNF), insulin-like growth factor (IGF)-1 and glial cell-derived neurotrophic factor (GDNF) are known to protect neuronal cell death in several neurodegenerative both in vitro and in vivo models. In this study, septal neurons were prepared from septal nucleus of embryonic (day 16-17) rat brain and treated with monomeric, oligomeric or fibrillar Aβ_1-42 peptide. Oligomeric Aβ_1-42, (10 μM) was the most potent at sublethal dose. Septal neuron cultures treated with BDNF, IGF-1 or GDNF or co-cultured with genetically modified human neural progenitor cells (hNPCs) secreting these neurotrophic factors (but not allowing contact between the two cell types), were protected from oligomeric Aβ_1-42 peptide-induced cell death, and these trophic factors enhanced cholinergic functions by increasing ChAT expression level. These results indicate the potential of employing transplanted hNPCs for treatment of AD.     

β-Amyloid 25-35 Peptide Reduces the Expression of Glutamine Transporter SAT1 in Cultured Cortical Neurons

β-Amyloid (Aβ) peptides may cause malfunction and death of neurons in Alzheimer’s disease. We investigated the effect of Aβ on key transporters of amino acid neurotransmission in cells cultured from rat cerebral cortex. The cultures were treated with Aβ(25-35) at 3 and 10 μM for 12 and 24 h followed by quantitative analysis of immunofluorescence intensity. In mixed neuronal–glial cell cultures (from P1 rats), Aβ reduced the concentration of system A glutamine transporter 1 (SAT1), by up to 50% expressed relative to the neuronal marker microtubule-associated protein 2 (MAP2) in the same cell. No significant effects were detected on vesicular glutamate transporters VGLUT1 or VGLUT2 in neurons, or on glial system N glutamine transporter 1 (SN1). In neuronal cell cultures (from E18 rats), Aβ(25-35) did not reduce SAT1 immunoreactivity, suggesting that the observed effect depends on the presence of astroglia. The results indicate that Aβ may impair neuronal function and transmitter synthesis, and perhaps reduce excitotoxicity, through a reduction in neuronal glutamine uptake. Special issue article in honor of Dr. Frode Fonnum.     

Chronic Exposure to High Levels of Zinc or Copper has Little Effect on Brain Metal Homeostasis or Aβ Accumulation in Transgenic APP-C100 Mice

Aberrant metal homeostasis may enhance the formation of reactive oxygen species and Aβ oligomerization and may therefore be a contributing factor in Alzheimer’s disease. This study investigated the effect of chronic high intake of dietary Zn or Cu on brain metal levels and the accumulation and solubility of Aβ in vivo, using a transgenic mouse model that over expresses the C-terminal containing Aβ fragment of human amyloid precursor protein but does not develop amyloid deposits. Exposure to chronic high Zn or Cu in the drinking water resulted in only slight elevations of the respective metals in the brain. Total Aβ levels were unchanged although soluble Aβ levels were slightly decreased, without visible plaque formation, enhanced gliosis, antioxidant upregulation or neuronal loss. This study indicates that brain metal levels are only marginally altered by long term oral exposure to extremely high Cu or Zn levels, and that this does not induce Aβ-amyloid formation in human Aβ expressing, amyloid-free mice, although this is sufficient to modulate Aβ solubility in vivo.