Terminal innervation of the male genitalia, cutaneous sensory receptors of the male foreskin.

PURPOSE: Understanding the types of sensory nerve termini within the glabrous skin of the human male foreskin could throw light on surgical outcomes and therapeutic possibilities for the future. Various receptor types sense changes in temperature, position, pressure, pain, light touch, itch, burning and pleasurable sexual sensations. Similarities and differences in innervation characteristics and density might become apparent when the glans penis is compared with homologous structures in the female genitalia. The aim of this study is to document the presence and characteristics of cutaneous sensory receptors in the human penile foreskin using a histopathological study of the nerve termini to achieve a more complete understanding of sensory experiences. METHODS: Foreskin samples were obtained from ten boys (aged 1-9 years) who had undergone circumcision. Informed consent was obtained from the parent/legal guardian. The samples were examined after modified Bielschowsky silver impregnation of neural tissue, and immunocytochemistry against gene protein product (PGP) 9.5 and neuron-specific enolase (NSE). RESULTS: PGP 9.5 appeared to be the most sensitive neural marker. Free nerve endings were identified in the papillary dermis visualized as thin fibers, mostly varicose, with either branched or single processes, either straight or bent. Two types of sensory corpuscle were identified: capsulated and non-capsulated. Meissner-like corpuscles were located in the papillary dermis. Capsulated corpuscles resembled typical Pacinian corpuscles, comprising a single central axon surrounded by non-neural periaxonic cells and lamellae. The capsulated corpuscles were strongly positive for PGP 9.5 and NSE. CONCLUSIONS: Free nerve endings, Meissner's corpuscles and Pacinian corpuscles are present in the human male foreskin and exhibit characteristic staining patterns.

Terminal innervation of female genitalia, cutaneous sensory receptors of the epithelium of the labia minora.

INTRODUCTION: Little information is available regarding the sensory nerve endings within the glabrous skin of the external female genitalia. The diversity of possible sensations suggests a variety of receptor types. Comprehensive knowledge of the sensory stimuli, including stimulus position, changes in temperature, pressure and pain, is critical for addressing pain and sexual function disorders clinically. The aim of this neuro-histological study is document the presence and characteristics of cutaneous sensory receptors in female genital tissue. MATERIALS AND METHODS: Labial skin samples were obtained from ten normal girls (aged 1-9 years). The specimens were waste tissue obtained during surgical intervention. They were all obtained by the senior investigator, a pediatric urologist, after the parent or legal guardian had given informed consent. The specimens were stained by Cajal-type silver impregnation and by immunocytochemistry against protein gene product (PGP) 9.5 and neuron-specific enolase (NSE). RESULTS: PGP 9.5 was the most sensitive neural marker for identifying cutaneous sensory receptors. Free nerve endings (FNEs) in the papillary dermis appeared as thin fibers, varicose, branched or single processed, straight or bent. In the labia minora, FNEs were identified in the strata basale, spinosum and granulosum of the epidermis. Non-capsulated (Meissner-like) corpuscles in the dermal papillae interdigitated with epidermal ridges of the skin. Capsulated corpuscles protruded from the deep dermis into the epidermis. Encapsulated corpuscles and cells located in the inner and outer cores were strongly positive for PGP 9.5. CONCLUSIONS: FNEs, Meissner's corpuscles and Pacinian corpuscles are present in the female labia minora and exhibit characteristic staining patterns.

c-Maf is required for the development of dorsal horn laminae III/IV neurons and mechanoreceptive DRG axon projections.

Establishment of proper connectivity between peripheral sensory neurons and their central targets is required for an animal to sense and respond to various external stimuli. Dorsal root ganglion (DRG) neurons convey sensory signals of different modalities via their axon projections to distinct laminae in the dorsal horn of the spinal cord. In this study, we found that c-Maf was expressed predominantly in the interneurons of laminae III/IV, which primarily receive inputs from mechanoreceptive DRG neurons. In the DRG, c-Maf⁺ neurons also coexpressed neurofilament-200, a marker for the medium- and large-diameter myelinated afferents that transmit non-noxious information. Furthermore, mouse embryos deficient in c-Maf displayed abnormal development of dorsal horn laminae III/IV neurons, as revealed by the marked reduction in the expression of several marker genes for these neurons, including those for transcription factors MafA and Rora, GABA(A) receptor subunit α5, and neuropeptide cholecystokinin. In addition, among the four major subpopulations of DRG neurons marked by expression of TrkA, TrkB, TrkC, and MafA/GFRα2/Ret, c-Maf was required selectively for the proper differentiation of MafA⁺/Ret⁺/GFRα2⁺ low-threshold mechanoreceptors (LTMs). Last, we found that the central and peripheral projections of mechanoreceptive DRG neurons were compromised in c-Maf deletion mice. Together, our results indicate that c-Maf is required for the proper development of MafA⁺/Ret⁺/GFRα2⁺ LTMs in the DRG, their afferent projections in the dorsal horn and Pacinian corpuscles, as well as neurons in laminae III/IV of the spinal cord.

Topographical Analysis of Pacinian Corpuscle in the Pulp of Human Cadaver Finger Tip Pulp: A Pilot Cadaver Study.

Background: The human hand is a specialised organ for fine motion and sensation and has a relatively large representation in the homunculus. The pathway of sensation starts from information sent by mechanoreceptors in the hand. This study reports the topography of the Pacinian corpuscle in the fingertips of a human cadaver. Methods: All 10 digits from both hands of a fresh-frozen cadaver were examined. Glabrous skin distal to the distal interphalangeal joint was harvested superficial to the periosteum including fat and subcutaneous tissue. The glabrous skin were divided into 10 sections that included five distal and five proximal sections. Modified gold chloride staining was performed. Sectioned specimens were observed under a light microscope and the density of Pacinian corpuscles was determined in each segment. The density of the corpuscles was compared between the radial/ulnar and proximal/distal segments and also between digits from the right hand versus those from the left hand. Results: Pacinian corpuscles were observed only in the subcutaneous tissue. There was no significant difference in density of the corpuscles between the distal and proximal segments or between the right and left hands. There was a statistically significant greater density of Pacinian corpuscles on the radial segments of all digits except the thumb. Conclusions: There is a greater density of Pacinian corpuscles on the radial side of the human fingertip in all digits except the thumb.

Innervation patterns of thumb trapeziometacarpal joint ligaments.

PURPOSE: The human thumb trapeziometacarpal (TM) joint is a unique articulation that allows stability during pinch and grip and great degrees of mobility. Because the saddle-shaped articulating surfaces of the TM joint are inherently unstable, joint congruity depends on the action of restraining ligaments and periarticular muscles. From other joints, it is known that proprioceptive and neuromuscular joint stability depend on afferent information from nerve endings within ligaments. We hypothesize that the TM joint ligaments may similarly be innervated, indicating a possible proprioceptive function of the joint. METHODS: We harvested 5 TM joint ligaments in entirety from 10 fresh-frozen cadaver hands with no or only minor signs of osteoarthritis and suture-marked them for proximal-distal orientation. The ligaments harvested were the dorsal radial, dorsal central, posterior oblique, ulnar collateral, and anterior oblique ligaments. After paraffin-sectioning, we stained the ligaments using a triple-antibody immunofluorescent technique and analyzed them using immunofluorescence microscopy. RESULTS: Using the triple-stain technique, mechanoreceptors could be classified as Pacinian corpuscles, Ruffini endings, or Golgi-like endings. The 3 dorsal ligaments had significantly more nerve endings than the 2 volar ligaments. Most of the nerve endings were close to the bony attachments and significantly closer (P = .010) to the metacarpal insertion of each ligament. The anterior oblique ligament had little to no innervation in any of the specimens analyzed. DISCUSSION: The TM joint ligaments had an abundance of nerve endings in the dorsal ligaments but little to no innervation in the anterior oblique ligament. The Ruffini ending was the predominant mechanoreceptor type, with a greater density in the mobile metacarpal portion of each ligament. CLINICAL RELEVANCE: Presence of mechanoreceptors in the dorsal TM joint ligaments infers a proprioceptive function of these ligaments in addition to their biomechanical importance in TM joint stability.

Differential localization of Acid-sensing ion channels 1 and 2 in human cutaneus pacinian corpuscles.

Acid-sensing ion channels (ASICs) are the members of the degenerin/epithelial sodium channel (Deg/ENaC) superfamily which mediate different sensory modalities including mechanosensation. ASICs have been detected in mechanosensory neurons as well as in peripheral mechanoreceptors. We now investigated the distribution of ASIC1, ASIC2, and ASIC3 proteins in human cutaneous Pacinian corpuscles using immunohistochemistry and laser confocal-scanner microscopy. We detected different patterns of expression of these proteins within Pacinian corpuscles. ASIC1 was detected in the central axon co-expressed with RT-97 protein, ASIC2 was expressed by the lamellar cells of the inner core co-localized with S100 protein, and ASIC3 was absent. These results demonstrate for the first time the differential distribution of ASIC1 and ASIC2 in human rapidly adapting low-threshold mechanoreceptors, and suggest specific roles of both proteins in mechanotransduction.

Heparan sulfate in human cutaneous Meissner's and Pacinian corpuscles.

Heparan sulfate proteoglycans are pericellular/cell surface molecules involved in somatosensory axon guidance in the peripheral nervous system. However, the distribution of heparan sulfate proteoglycans in the extracellular matrix of human cutaneous sensory corpuscles is unknown. Immunohistochemistry and immunofluorescence assays were performed to define the localization of heparan sulfate proteoglycans in human cutaneous Meissner's and Pacinian corpuscles using two anti-heparan sulfate antibodies together with anti-S100 protein, anti-PGP9.5, anti-CD34 (to immunolabel basement membranes, Schwann cells, axon and the intermediate endoneurial layer of Pacinian corpuscles, respectively), anti-Type IV collagen, and anti-chondroitin sulfate antibodies. Heparan sulfate proteoglycans were colocalized with Type IV collagen in Meissner's corpuscles and were located in the outer core lamellae and capsule, but not in the inner core or the intermediate layer, in Pacinian corpuscles. Chondroitin sulfate was observed in the intermediate layer of Pacinian corpuscles but was never colocalized with heparan sulfate proteoglycans. The present results strongly suggest that heparan sulfate proteoglycans are associated with the basement membranes of the lamellar cells in Meissner's corpuscles and with the complex outer core capsule in Pacinian corpuscles. The functional significance of these results, if any, remains to be elucidated.

Myelin basic protein-positive nerve fibres in human Meissner corpuscles.

Myelinated nerve fibres forming sensory corpuscles become amyelinic before entering the corpuscle. Interestingly, in Meissner corpuscles from monkey myelin basic protein (MBP), a specific component of myelin sheath co-localized with neuronal markers. To investigate whether or not this also occurs in human digital Meissner corpuscles, we used single and double immunohistochemistry to detect MBP associated with axonic (protein gene product (PGP) 9.5) or Schwann and Schwann-related cell (S100 protein) markers. We also studied these markers in Pacinian corpuscles. Nerve fibres immunoreactive for MBP were detected in about 25% of the Meissner corpuscles examined; however, MBP never co-localized with PGP 9.5 and MBP occasionally co-localized with S100 protein. MBP-immunoreactive fibres associated with Meissner corpuscles were observed at the periphery of the lamellar cells or within the corpuscle between the lamellar cells. These results describe the distribution of myelinated nerve fibres expressing MBP in human Meissner corpuscles, which is important when studying Meissner corpuscles in cutaneous biopsies used for the diagnosis of peripheral and degenerative neuropathies.

Chondroitin Sulfate in Human Cutaneous Meissner and Pacinian Sensory Corpuscles.

Chondroitin sulfate is a glycosaminoglycan involved in maintaining the morphofunctional properties of the extracellular matrix in peripheral nerves, but its distribution in human sensory corpuscles is unknown despite the role of extracellular matrix in mechanotransduction and axonal guidance. In this study we used immunohistochemistry to analyze the distribution of chondroitin sulfate in human cutaneous Meissner and Pacinian corpuscles. Chondroitin sulfate expression was absent from Meissner corpuscles. In Pacinian corpuscles chondroitin sulfate was found associated to a CD34 positive endoneurial-related layer, interposed between the S100 protein positive inner core cells, and the vimentin positive inner core and outer core-capsule cells. Therefore, the intermediate CD34+/chondroitin sulfate+ intermediate layer present in Pacinian corpuscles isolates the neural segment of the corpuscles (axon and inner core) from the non-neural segments (outer core and capsule). These results suggest a role of chondroitin sulfate in the proper axonal growth and guidance, within the neuronal compartment of the Pacinian corpuscles during development and reinnervation, can be hypothesized. Moreover, a role of CS in mechanotransduction cannot be ruled out. Anat Rec, 302:325-331, 2019. © 2018 Wiley Periodicals, Inc.

A finite-element model of mechanosensation by a Pacinian corpuscle cluster in human skin.

The Pacinian corpuscle (PC) is the cutaneous mechanoreceptor responsible for sensation of high-frequency (20-1000 Hz) vibrations. PCs lie deep within the skin, often in multicorpuscle clusters with overlapping receptive fields. We developed a finite-element mechanical model of one or two PCs embedded within human skin, coupled to a multiphysics PC model to simulate action potentials elicited by each PC. A vibration was applied to the skin surface, and the resulting mechanical signal was analyzed using two metrics: the deformation amplitude ratio ([Formula: see text], [Formula: see text] and the phase shift of the vibration ([Formula: see text], [Formula: see text] between the stimulus and the PC. Our results showed that the amplitude attenuation and phase shift at a PC increased with distance from the stimulus to the PC. Differences in amplitude ([Formula: see text] and phase shift ([Formula: see text] between the two PCs in simulated clusters directly affected the interspike interval between the action potentials elicited by each PC ([Formula: see text]. While [Formula: see text] had a linear relationship with [Formula: see text], [Formula: see text]'s effect on [Formula: see text] was greater for lower values of [Formula: see text]. In our simulations, the separation between PCs and the distance of each PC from the stimulus location resulted in differences in amplitude and phase shift at each PC that caused [Formula: see text] to vary with PC location. Our results suggest that PCs within a cluster receive different mechanical stimuli which may enhance source localization of vibrotactile stimuli, drawing parallels to sound localization in binaural hearing.

Pacinian Corpuscles in the Human Fetal Finger and Thumb: A Study Using 3D Reconstruction and Immunohistochemistry.

The detailed distribution of Pacinian corpuscles was evaluated by viewing the transverse sections of all fingers and thumbs, including the interdigital areas, from eight hands of five fetuses of gestational age 28-33 weeks (crown-rump length 230-290 mm). Among the 40 fingers and thumbs, serial sections were prepared for 3D reconstructions of nerve elements in the distal and middle phalangeal segments of three fifth fingers; in these three fingers, the distal segment contained 45-75 Pacinian corpuscles. These Pacinian corpuscles were 0.2-1.0 mm in length and 0.05-0.3 mm in thickness, oriented along the proximodistal axis and arranged along the palmar digital nerve branches. Other than beneath the digital skin, small corpuscles (<0.1 mm in thickness) were observed within the tendon sheath of the flexors in the middle or distal segment of five fetuses and in the nail beds of four fetuses. Clusters of 5-20 corpuscles formed bouquet- or tree-like arrangements along neurovascular bundles in the fingers, thumbs and interdigital areas. Because the space beneath the skin was thick and loose in the interdigital area, trees in the interdigital area were up to 2 mm long. Regardless of site, the central core of each corpuscle was positive for S100 protein, while the core and parts of the capillaries in the corpuscle were weakly positive for nestin. Because corpuscles in the tendon sheath and nail bed, as well as bouquet- and tree-like arrangements of corpuscles, have not been reported in adults, these morphologies are likely specific to fetuses. Anat Rec, 2017. © 2017 Wiley Periodicals, Inc. Anat Rec, 301:154-165, 2018. © 2017 Wiley Periodicals, Inc.

Endoneurial-CD34 positive cells define an intermediate layer in human digital Pacinian corpuscles.

The endoneurial and/or perineurial origin of the outer core; i.e. the concentric and continuous lamellae located outside the complex formed by the axon and the Schwann-related cells, in human Pacinian corpuscles is still debated. Here we used immunohistochemistry coupled with a battery of antibodies to investigate the expression of perineurial (Glucose transporter 1 and epithelial membrane antigen) or endoneurial (CD34 antigen) markers in human digital Pacinian corpuscles. CD34 immunoreactivity was restricted to one layer immediately outside the inner core, whereas the proper outer core displayed antigens typical of the perineurial cells. These results demonstrate an intermediate endoneurial layer that divides the Pacinian corpuscles into two distinct compartments: the avascular inner neural compartment (formed by the axon and the Schwann-related cells that form the inner core), and the outer non-neural compartment (formed by the outer core). The functional relevance of these findings, if any, remains to be clarified.

Bcl-2 immunoreactivity in human cutaneous Meissner and Pacinian corpuscles.

The occurrence and distribution of Bcl-2, a protein involved in the death-life cell pathways, was investigated in the peripheral sensory nervous system of healthy adult humans, including lumbar dorsal root ganglia, nerve trunks and glabrous skin (to analyze sensory corpuscles) using Western blot and immunohistochemistry. The antibody used labelled a protein of 26 kDa of estimated molecular weight corresponding with Bcl-2. Immunohistochemistry showed that only a neuronal population in dorsal root ganglia, some axons in peripheral nerves and the axon supplying Meissner and Pacinian corpuscles contained Bcl-2, whereas peripheral glial cells (i.e. satellite glial cells, Schwann cell, and lamellar cells of sensory corpuscles) did not. These results suggest that in normal conditions, Bcl-2 is only present in some neuronal, but not glial, elements of the sensory peripheral nervous system. The functional significance, if any, of these results remains to be determined.

Sanshool on The Fingertip Interferes with Vibration Detection in a Rapidly-Adapting (RA) Tactile Channel.

An Asian spice, Szechuan pepper (sanshool), is well known for the tingling sensation it induces on the mouth and on the lips. Electrophysiological studies have revealed that its active ingredient can induce firing of mechanoreceptor fibres that typically respond to mechanical vibration. Moreover, a human behavioral study has reported that the perceived frequency of sanshool-induced tingling matches with the preferred frequency range of the tactile rapidly adapting (RA) channel, suggesting the contribution of sanshool-induced RA channel firing to its unique perceptual experience. However, since the RA channel may not be the only channel activated by sanshool, there could be a possibility that the sanshool tingling percept may be caused in whole or in part by other sensory channels. Here, by using a perceptual interference paradigm, we show that the sanshool-induced RA input indeed contributes to the human tactile processing. The absolute detection thresholds for vibrotactile input were measured with and without sanshool application on the fingertip. Sanshool significantly impaired detection of vibrations at 30 Hz (RA channel dominant frequency), but did not impair detection of higher frequency vibrations at 240 Hz (Pacinian-corpuscle (PC) channel dominant frequency) or lower frequency vibrations at 1 Hz (slowly adapting 1 (SA1) channel dominant frequency). These results show that the sanshool induces a peripheral RA channel activation that is relevant for tactile perception. This anomalous activation of RA channels may contribute to the unique tingling experience of sanshool.

Mechanoreceptors in the Anterior Horn of the Equine Medial Meniscus: an Immunohistochemical Approach.

Lameness due to stifle and especially meniscal lesions is frequent in equine species. In humans, mechanoreceptors involved in proprioceptive function are well studied. Given the high incidence of meniscal injuries in horses, and the lack of information concerning them in equine menisci, our objective was to study these corpuscles in six healthy anterior horns of the equine medial meniscus, which is the most common localisation reported for equine meniscal injuries. Immunohistochemical stainings were performed using antibodies against high molecular weight neurofilaments and glial fibrillary acidic proteins. From a purely fundamental point of view, our work highlights for the first time the presence of Ruffini, Pacini and Golgi corpuscles in equine meniscus. They were found, isolated or in clusters and always located at the vicinity of blood vessels, at the level of the anterior horn of the equine medial meniscus. This morphological approach could serve as a basis for clinical studies, to evaluate the impact of these corpuscles on the poor sportive prognosis in equine meniscal tears.

Brain-derived neurotrofic factor and its receptor TrkB are present, but segregated, within mature cutaneous Pacinian corpuscles of Macaca fascicularis.

Some mechanoreceptors in mammals depend totally or in part on the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT-4), and their receptor TrkB, for development and maintenance. These actions are presumably exerced regulating the survival of discrete sensory neurons in the dorsal root ganglia which form mechanoreceptors at the periphery. In addition, the cells forming the mechanoreceptors also express both neurotrophins and their receptors although large differences have been described among species. Pacinian corpuscles are rapidly adapting low-threshold mechanoreceptors whose dependence from neurotrophins is not known. In the present study, we analyzed expression of TrkB and their ligands BDNF and NT-4 in the cutaneous Pacinian corpuscles of Macaca fascicularis using immunohistochemistry and fluorescent microscopy. TrkB immunoreactivity was found in Pacinian corpuscles where it co-localized with neuron-specific enolase, and occasionally with S100 protein, thus suggesting that TrkB expression is primarily into axons but also in the lamellar cells and even in the outer core. On the other hand, BDNF immunoreactivity was found the inner core cells where it co-localized with S100 protein but also in the innermost layers of the outer core; NT-4 immunostaining was not detected. These results describe for the first time the expression and distribution of a full neurotrophin system in the axon-inner core complex of mature Pacinian corpuscles. The data support previous findings demonstrating large differences in the expression of BDNF-TrkB in mammalian mechanoreceptors, and also suggest the existence of a retrograde trophic signaling mechanism to maintain morphological and functional integrity of sensory neurons supplying Pacinian corpuscles.

Immunohistochemistry of human cutaneous Meissner and pacinian corpuscles.

This paper reviews the immunohistochemical characteristics of two kinds of human cutaneous sensory nerve formations (SNFs), the Meissner and Pacinian corpuscles. In both kinds of SNF the central axon might be easily identifiable because it displays immunoreactivity (IR) for the neuroendocrine markers neuron-specific enolase and protein gene product 9.5, as well as for neuron-specific intermediate filament proteins, i.e., neurofilaments. Other intermediate filament proteins such as vimentin are localized in the lamellar cells of Meissner corpuscles, and in the inner core, outer core and capsule of Pacinian corpuscles. However, they lack cytokeratins or glial fibrillary acidic protein IR. On the other hand, and in agreement with ultrastructural data, IR for basement membrane constituents laminin and type IV collagen is found underlying all SNF constituents, with the exception of the axon. One of the mechanisms involved in the maintenance of intracellular calcium ions (Ca2+) homeostasis is the calcium binding proteins. Ca2+ play a key role in the mechanoelectric transduction and have been localized in SNFs. In this way IR for the Ca(2+)-binding proteins calbindin D28K, parvalbumin and calretinin, is present and colocalized in both Meissner and Pacinian corpuscles; furthermore, S-100 protein is exclusively localized in the lamellar cells and the inner core. On the other hand, the skin is a main source of neurotrophins for a subset of neural crest sensory neurons, some of which end forming SNF. These factors are conveyed via retrograde axonal transport from the skin to the cell body of the responsive neurons. Interestingly, Meissner and Pacinian corpuscles also display IR for the pan-neurotrophin low-affinity receptor (p75), and for the trkA receptor protein, a basic constituent of the high-affinity receptor for some neurotrophins. Moreover, they express IR for the epidermal growth factor receptor. Finally, other antigens not proper to the cells forming human cutaneous SNF, such as the epithelial membrane antigen and the leucocytary antigen-7, have also been detected.

Localization of beta and gamma subunits of ENaC in sensory nerve endings in the rat foot pad.

The molecular mechanisms underlying mechanoelectrical transduction and the receptors that detect light touch remain uncertain. Studies in Caenorhabditis elegans suggest that members of the DEG/ENaC cation channel family may be mechanoreceptors. Therefore, we tested the hypothesis that subunits of the mammalian epithelial Na(+) channel (ENaC) family are expressed in touch receptors in rat hairless skin. We detected betaENaC and gammaENaC, but not alphaENaC transcripts in cervical and lumbar dorsal root ganglia (DRG). Using immunofluorescence, we found betaENaC and gammaENaC expressed in medium to large lumbar DRG neurons. Moreover, we detected these two subunits in Merkel cell-neurite complexes, Meissner-like corpuscles, and small lamellated corpuscles, specialized mechanosensory structures of the skin. Within these structures, betaENaC and gammaENaC were localized in the nerve fibers believed to contain the sensors responsive to mechanical stress. Thus beta and gammaENaC subunits are good candidates as components of the molecular sensor that detects touch.

Beta-amyloid precursor protein in human digital skin.

The occurrence and distribution of beta-amyloid precursor protein (beta APP) and of beta-amyloid peptide (beta/A4) was investigated using immunoblotting and immunohistochemical techniques in the digital skin of healthy adult subjects. beta APP-like proteic bands with apparent molecular masses between 55-60 kDa, 100-125 kDa (corresponding to the full-length beta APP isoforms), 145-150 kDa, and 200 kDa were found in pellets and supernatants of whole skin and dermis. The same proteins, except that of approximately 200 kDa, were also found in pellets from the epidermis, whereas epidermic supernatants were unreactive. beta/A4 was not found by immunoblotting. Light microscope immunohistochemistry showed beta APP immunoreactivity (IR) in: (a) dermal nerves; (b) lamellar cells of Meissner, as well as inner-core, outer-core and capsule of Pacinian corpuscles; and (c) dermal blood vessels, sweat glands and, occasionally, epidermis. The distribution of beta/A4 IR matched that of beta APP, and no evidence of extracellular beta/A4 IR was encountered. Present results demonstrate that beta APP, but not beta/A4, is normally present in human glabrous (digital) skin. The potential clinical relevance of these findings is discussed.