Neurotrophin-4 mediated TrkB activation reinforces morphine-induced analgesia.
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Analgesia↗
Biomedical subjects
Tibor Harkany
Publications and source records attributed to Tibor Harkany.
Complementary distribution of type 1 cannabinoid receptors and vesicular glutamate transporter 3 in basal forebrain suggests input-specific retrograde signalling by cholinergic neurons.
Basal forebrain cholinergic neurons project to diverse cortical and hippocampal areas and receive reciprocal projections therefrom. Maintenance of a fine-tuned synaptic communication between pre- and postsynaptic cells in neuronal circuitries also requires feedback mechanisms to control the probability of neurotransmitter release from the presynaptic terminal. Release of endocannabinoids or glutamate from a postsynaptic neuron has been identified as a means of retrograde synaptic signalling. Presynaptic action of endocannabinoids is largely mediated by type 1 cannabinoid (CB1) receptors, while fatty-acid amide hydrolase (FAAH) is involved in inactivating some endocannabinoids postsynaptically. Alternatively, vesicular glutamate transporter 3 (VGLUT3) controls release of glutamate from postsynaptic cells. Here, we studied the distribution of CB1 receptors, FAAH and VGLUT3 in cholinergic basal forebrain nuclei of mouse and rat. Cholinergic neurons were devoid of CB1 receptor immunoreactivity. A fine CB1 receptor-immunoreactive (ir) fibre meshwork was present in medial septum, diagonal bands and nucleus basalis. In contrast, the ventral pallidum and substantia innominata received dense CB1 receptor-ir innervation and cholinergic neurons received CB1 receptor-ir presumed synaptic contacts. Consistent with CB1 receptor distribution, FAAH-ir somata were abundant in basal forebrain and appeared in contact with CB1 receptor-containing terminals. Virtually all cholinergic neurons were immunoreactive for FAAH. A significant proportion of cholinergic cells exhibited VGLUT3 immunoreactivity in medial septum, diagonal bands and nucleus basalis, and were in close apposition to VGLUT3-ir terminals. VGLUT3 immunoreactivity was largely absent in ventral pallidum and substantia innominata. We propose that specific subsets of cholinergic neurons may utilize endocannabinoids or glutamate for retrograde control of the efficacy of input synapses, and the mutually exclusive complementary distribution pattern of CB1 receptor-ir and VGLUT3-ir fibres in basal forebrain suggests segregated input-specific signalling mechanisms by cholinergic neurons.
Amidohydrolases↗
In vivo labeling of rabbit cholinergic basal forebrain neurons with fluorochromated antibodies.
Cholinergic basal forebrain neurons (CBFN) expressing the low-affinity neurotrophin receptor p75 (p75(NTR)) were previously selectively labeled in vivo with carbocyanine 3 (Cy3)-tagged anti-p75(NTR), but the applied 192IgG-conjugates recognized p75(NTR) only in rat. The antibody ME 20.4 raised against human p75(NTR) had been shown to cross-react with the receptor in monkey, raccoon, sheep, cat, dog, pig and rabbit. Hence, for in vivo labeling of rabbit CBFN in the present study, ME 20.4 was fluorochromated with Cy3-N-hydroxysuccinimide ester and purified Cy3-ME 20.4 was injected intracerebroventricularly. Two days post-injection, clusters of Cy3-ME 20.4 were found in CBFN displaying choline acetyltrans-ferase-immunoreactivity. Following photoconversion, electron microscopy revealed fluorochromated antibodies in secondary lysosomes. In conclusion, Cy3-ME 20.4 might become an appropriate marker for CBFN in live and fixed tissues of various mammalian species.
Animals↗
Distinct subsets of nucleus basalis neurons exhibit similar sensitivity to excitotoxicity.
Excitotoxic lesions in the magnocellular nucleus basalis (MBN) lead to a significant damage of cholinergic neurons concomitant with increased amyloid precursor protein (APP) expression in the cerebral cortex. However, the sensitivity of non-cholinergic neurons to excitotoxicity, and changes of APP expression in the damaged MBN are still elusive. Hence, we performed multiple-labeling immunocytochemistry for choline-acetyltransferase (ChAT), neuron-specific nuclear protein (NeuN) and APP 4, 24, and 48 h after NMDA infusion in the MBN. Whereas all cholinergic neurons were immunoreactive for NeuN, this neuronal marker also labeled a population of ChAT-immunonegative non-cholinergic neurons. Both neuron populations exhibited a similar degree of sensitivity to NMDA excitotoxicity that became evident as early as 4 h post-lesion. Cholinergic MBN neurons showed abundant APP immunoreactivity (approximately 90%), while only a fraction (approximately 20-30%) of non-cholinergic neurons expressed the protein. Remarkably, cholinergic but not non-cholinergic neurons retained their APP immunoreactivity after NMDA infusion. In conclusion, cholinergic MBN neurons are not preferentially sensitive to short-term excitotoxicity, but are one of the major sources of APP in the basal forebrain.
Acetylcholine↗
Cutaneous lymphatic amyloid deposits in "Hungarian-type" familial transthyretin amyloidosis: a case report.
Multiple transthyretin (TTR) mutations have recently been identified and implicated in the development of familial systemic amyloidoses, but early diagnosis of these disorders is still largely unresolved. We investigated the presence and tissue distribution of TTR-derived amyloid in skin biopsies of a 59-year-old woman carrying the "Hungarian-type" mutation of TTR (Asp18Gly). Clinical symptoms involved severe central nervous system dysfunction without signs of polyneuropathy, also referred to as the "central form" of TTR-related systemic amyloidosis. Skin biopsy was also evaluated as a tool in order to diagnose this type of TTR amyloidosis. Biopsy samples were collected from the infra-axillary region. Light microscopy using Congo red and polarized light was used to diagnose amyloid deposits. Subsequently, electron microscopic analysis was performed to correlate the amyloid deposits with vicinal dermal structures. The amyloid class was determined by means of immunocytochemistry. TTR amyloid was primarily localized to lymphatic microvessels in the present case, whereas arterioles were devoid of TTR amyloid deposits. In addition, the well-known association of TTR amyloid with neural structures along the erector pilorum and around the sebaceous and serosal (sweat) glands was also evident. Electron microscopic analysis of amyloid deposits revealed characteristic amyloid fibrils that were irregular in shape, and exhibited a heterogeneous density and a random deposition pattern. Immunocytochemistry confirmed the cutaneous accumulation of TTR amyloid. In conclusion, amyloid deposits were abundantly present in the skin of a patient with "Hungarian-type" TTR amyloidosis; skin biopsy seems to be appropriate for the diagnosis of this disorder. We showed that besides the erector pilorum, sweat glands and nerve terminals, lymphatic microvessels are also severely infiltrated by TTR amyloid. Whether these pathological alterations can exclusively be found in "Hungarian-type" TTR amyloidosis should still be investigated. If such changes are not specific for the Asp18Gly mutation, they may be considered as diagnostic markers for "central" TTR amyloid disorders.
Amyloidosis↗
Functional recovery of cholinergic basal forebrain neurons under disease conditions: old problems, new solutions?
Recognition of the involvement of cholinergic neurons in the modulation of cognitive functions and their severe dysfunction in neurodegenerative disorders, such as Alzheimer's disease, initiated immense research efforts aimed at unveiling the anatomical organization and cellular characteristics of the basal forebrain (BFB) cholinergic system. Concomitant with our unfolding knowledge about the structural and functional complexity of the BFB cholinergic projection system, multiple pharmacological strategies were introduced to rescue cholinergic nerve cells from noxious attacks; however, a therapeutic breakthrough is still awaited. In this review, we collected recent findings that significantly contributed to our better understanding of cholinergic functions under disease conditions, and to the design of effective means to restore lost or damaged cholinergic functions. To this end, we first provide a brief survey of the neuroanatomical organization of BFB nuclei with emphasis on major evolutionary differences among mammalian species, in particular rodents and primates, and discuss limitations of the translation of experimental data to human therapeutic applications. Subsequently, we summarize the involvement of cholinergic dysfunction in the pathogenesis of severe neurological conditions, including stroke, traumatic brain injury, virus encephalitis and Alzheimer's disease, and emphasize the critical role of pro-inflammatory cytokines as common mediators of cholinergic neuronal damage. Moreover, we review leading functional concepts on the limited recovery of cholinergic neurons and their impaired plastic re-modeling, as well as on the hampered interplay of the ascending cholinergic and monoaminergic projection systems under neurodegenerative conditions. In addition, recent advances in the dynamic labeling of living cholinergic neurons by fluorochromated antibodies, referred to as in vivo labeling, and novel neuroimaging approaches as potential diagnostic tools of progressive cholinergic decline are surveyed. Finally, the potential of cell replacement strategies using embryonic and adult stem cells, and multipotent neural progenitors, as a means to recover damaged cholinergic functions, is discussed.
Acetylcholine↗
Pathological peptide folding in Alzheimer's disease and other conformational disorders.
Main neuropathological hallmarks of Alzheimer's disease (AD) and other neurodegenerative disorders are the deposition of neurofibrillary tangles consisting of abnormally phosphorylated protein tau and of senile plaques largely containing insoluble beta-amyloid peptides (A beta), containing up to 43 amino acid residues derived from the beta-amyloid precursor protein. Such A beta-sheets become visible by using suitable histochemical methods. Molecular simulation showed that the central, alpha-helical, lipophilic, antigenic folding domain of the A beta-peptide loop is a promising molecular target of beta-sheet breakers that thus prevent the polymerization of A beta into aggregates. It seems that di- and tetramers of A beta-peptides have a beta-barrel- like structure. In the present review, an optimized neural network analysis was applied to recognize possible structure-activity relationships of peptidomimetic beta-sheet breakers. The anti-aggregatory potency of beta-sheet breakers largely depends upon their total, electrostatic, and hydration energy as derived from their geometry-optimized conformations using the hybrid Gasteiger-molecular mechanics approach. Moreover, we also summarize peptide misfolding in several disorders with distinct clinical symptoms, including prion diseases and a broad variety of systemic amyloidoses, as the common pathogenic step driving these disorders. In particular, conversion of nontoxic alpha-helix/random-coils to beta-sheet conformation was recognized as being critical in producing highly pathogenic peptide assemblies. Whereas conventional pharmacotherapy of AD is mainly focused on restoring cholinergic activity and diminishing inflammatory responses as a consequence of amyloid accumulation, we here survey potential approaches aimed at preventing or reserving the transition of neurotoxic peptide species from alpha-helical/random coil to beta-sheet conformation and thus abrogating their effects in a broad variety of disorders.
Alzheimer Disease↗