Biomedical subjects

E J Mufson

Publications and source records attributed to E J Mufson.

At least 37 records · Page 2Linked to original sources

PubMed1999

Preservation of nucleus basalis neurons containing choline acetyltransferase and the vesicular acetylcholine transporter in the elderly with mild cognitive impairment and early Alzheimer's disease.

Immunocytochemistry for choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT) was used to examine the expression of these linked cholinergic markers in human basal forebrain, including cases with early stages of Alzheimer's disease (AD). Previous neurochemical studies have measured decreased ChAT activity in terminal fields, but little change or even increased levels of VAChT. To determine total cholinergic neuron numbers in the nucleus basalis of Meynert (nbM), stereologic methods were applied to tissue derived from three groups of individuals with varying levels of cognition: no cognitive impairment (NCI), mild cognitive impairment (MCI), and early-stage Alzheimer's disease (AD). Both markers were expressed robustly in nucleus basalis neurons and across all three groups. On average, there was no significant difference between the number of ChAT- (210,000) and VAChT- (174, 000) immunopositive neurons in the nbM per hemisphere in NCI cases for which the biological variation was calculated to be 17%. There was approximately a 15% nonsignificant reduction in the number of cholinergic neurons in the nbM in the AD cases with no decline in MCI cases. The number of ChAT- and VAChT-immunopositive neurons was shown to correlate significantly with the severity of dementia determined by scores on the Mini-Mental State Examination, but showed no relationship to apolipoprotein E allele status, age, gender, education, or postmortem interval when all clinical groups were combined or evaluated separately. These data suggest that cholinergic neurons, and the coexpression of ChAT and VAChT, are relatively preserved in early stages of AD.

Aged↗

PubMed1999

Dopamine transporter-immunoreactive neurons decrease with age in the human substantia nigra.

Unbiased disector stereologic cell counting was applied to sections from the human substantia nigra that were immunostained by using a monoclonal antibody against the dopamine transporter (DAT). This antibody was found to penetrate the full thickness of the stained section. Quantification of the number of DAT immunostained neurons was performed in human cases stratified into three age groups, young (ages 0-49 years), middle aged (ages 50-69 years), and aged (ages 70-85 years). The number of DAT-immunoreactive nigral neurons was normalized for each case by constructing a ratio of the number of DAT-containing neurons to total number of neuromelanin-containing cells in each subject's sample. Three types of DAT nigral neurons were seen: type 1, intensely stained; type 2, lightly stained; and type 3, DAT-immunonegative neuromelanin-containing perikarya. By 50 years of age, the number of type 1 neurons decreased significantly (P < 0.0001), whereas the number of type 2 neurons increased with age (P < 0.0001). Type 3 neurons also increased with age (P < 0.01), although less robustly than type 2 neurons. Type 1 neurons decreased by 11.2% per decade, and the total number of nigral neurons (types 1-3) decreased by 6.7% per decade. Relative to the young group, there were 75% and 88% reductions in type 1 neurons in the middle-aged and aged groups, respectively. This contrasts with the 35% and 41% reductions in total number of neuromelanin-containing neurons seen in middle-aged and aged groups, respectively. The young group had significantly more type 1 neurons and fewer type 2 neurons compared with middle-aged and aged participants. Post-hoc analyses indicated that the young group had significantly fewer type 3 neurons compared with middle-aged and aged participants. These findings demonstrate an age-related reduction in the number of substantia nigra DAT-immunoreactive neurons. Therefore, insight into the mechanisms regulating the rate of DAT synthesis may aid in our understanding of the decline of DATs with aging and its functional significance.

Adolescent↗

PubMed1999

Immunocytochemical localization of the dopamine transporter in human brain.

The dopamine transporter (DAT) was localized in normal human brain tissue by light microscopic immunocytochemistry by using highly specific monoclonal antibodies. Regional distribution of DAT was found in areas with established dopaminergic circuitry, e.g., mesostriatal, mesolimbic, and mesocortical pathways. Mesencephalic DAT-immunoreactivity was enriched in the dendrites and cell bodies of neurons in the substantia nigra pars compacta and ventral tegmental area. Staining in the striatum and nucleus accumbens was dense and heterogeneous. Mesocortical DAT immunoreactivity in motor, premotor, anterior cingulate, prefrontal, entorhinal/perirhinal, insular, and visual cortices was detected in scattered varicose and a few nonvaricose fibers. Varicose fibers were relatively enriched in the basolateral and central subnuclei of amygdala, with sparser fibers in lateral and basomedial subnuclei. Double-labeling studies combining DAT and tyrosine hydroxylase (TH) immunostaining in the ventral mesencephalon showed two subpopulations of dopaminergic neurons differentiated by the presence or absence of DAT-immunoreactivity in the A9 and A10 cell groups. In other dopaminergic cell groups (All, A13-A15), TH-positive hypothalamic neurons showed no detectable DAT-immunoreactivity. However, fine DAT-immunoreactive axons were scattered throughout the hypothalamus, particularly concentrated along the medial border, with more coarse axons present along the lateral border. These findings demonstrate that most mesotelencephalic dopamine neurons of human brain express high levels of DAT throughout their entire somatodendritic and axonal domains, whereas a smaller subpopulation of mesencephalic dopamine cells and all hypothalamic dopamine cell groups examined express little or no DAT. These data indicate that different subpopulations of dopaminergic neurons use different mechanisms to regulate their extracellular dopamine levels.

Adolescent↗

PubMed1999

Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson's disease.

As part of a safety and tolerability study, a 65-year-old man with Parkinson's disease (PD) received monthly intracerebroventricular injections of glial-derived neurotrophic factor (GDNF). His parkinsonism continued to worsen following intracerebroventricular GDNF treatment. Side effects included nausea, loss of appetite, tingling, L'hermitte's sign, intermittent hallucinations, depression, and inappropriate sexual conduct. There was no evidence of significant regeneration of nigrostriatal neurons or intraparenchymal diffusion of the intracerebroventricular GDNF to relevant brain regions. Alternative GDNF delivery systems should be explored.

Aged↗

PubMed1999

Entorhinal cortex beta-amyloid load in individuals with mild cognitive impairment.

The deposition of beta-amyloid within the entorhinal cortex (EC) may play a key role in the development of mild cognitive impairment (MCI) in the elderly. To examine the relationship of beta-amyloid deposition to MCI, EC tissue immunostained for this protein was quantitated from a cohort of aged Catholic religious clergy with a clinical diagnosis of MCI and compared to those with no cognitive impairment (NCI) and Alzheimer's disease (AD). beta-amyloid staining was seen in 12 of the 20 NCI, in 10 of 12 MCI, and in all 12 AD cases within the EC. beta-amyloid immunoreactivity displayed two patterns within the EC: (1) a crescent-shaped band within layers 3-4 or (2) bilaminar staining mainly within layers 2-3 and 5-6. Ten cases failed to display any detectable beta-amyloid imunoreactivity. Despite the heterogeneity of beta-amyloid loads within the clinical groups, decomposing an analysis of variance revealed a significant difference across groups in mean beta-amyloid load within the EC based upon a linear trend analysis. Multiple comparisons testing revealed that NCI individuals had a significantly lower mean beta-amyloid load (1.32) than AD individuals (4.55). The MCI individuals had a mean intermediate (2.60) load between NCI and AD, but not statistically distinguishable from the mean for either NCI or AD. Spearman rank correlation showed a trend for decreasing MMSE with increasing amyloid load that failed to reach statistical significance. Since many NCI cases displayed beta-amyloid loads equal to or greater than that seen in some MCI and some AD cases, it is mostly likely that deposition of this protein is not the sole pathogenic event underlying cognitive impairment in the elderly.

Aged↗

PubMed1999

Distribution and retrograde transport of trophic factors in the central nervous system: functional implications for the treatment of neurodegenerative diseases.

Neurotrophins play a crucial role in the maintenance, survival and selective vulnerability of various neuronal populations within the normal and diseased brain. Several families of growth promoting substances have been identified within the central nervous system (CNS) including the superfamily of nerve growth factor related neurotrophin factors, glial derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF). In addition, other non-neuronal growth factors such as fibroblast growth factor (FGF) have also been identified. This article reviews the trophic anatomy of these factors within the CNS. Intraventricular and intraparenchymal injections of exogenous nerve growth factor result in retrograde labeling mainly within the cholinergic basal forebrain. Distribution of brain derived neurotrophic factor (BDNF) following intraventricular injection is minimal due to the binding to the trkB receptor along the ventricular wall. In contrast, intraparenchymal injections of BDNF results in widespread retrograde transport throughout the CNS. BDNF has also been shown to be transported anterogradely within the CNS. Infusion of GDNF into the CNS results in retrograde transport limited to the nigrostriatal pathway. Hippocampal injections of NT-3 retrogradely label mainly basal forebrain neurons. Retrograde transport of radiolabeled CNTF has only been observed in sensory neurons of the sciatic nerve. Following intraventricular and intraparenchymal infusion of radiolabeled bFGF, retrograde neuronal labeling was found in the telecephalon, diencephalon, mesencephalon and pons. In contrast retrograde labeling for aFGF was found only in the hypothalamus and midbrain. Since select neurotrophins traffic anterogradely and retrogradely within the nervous system, these proteins could be used to treat neurological diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.

Animals↗

PubMed1998

Galanin expression within the basal forebrain in Alzheimer's disease. Comments on therapeutic potential.

The inhibitory neuropeptide galanin has widespread distribution throughout the central nervous system. Studies indicate that galanin modulates cognition by regulating cholinergic basal forebrain (CBF) neuron function. The chemoanatomic organization of galanin within the mammalian CBF differs across species. In monkeys, all CBF neurons coexpress galanin, whereas in apes and humans galanin is found within a separate population of interneurons that are in close apposition to the CBF perikarya. Pharmacologic investigations revealed a low and high affinity galanin receptor within the basal forebrain in humans. In vitro autoradiographic investigations of the primate brain indicate that galanin receptors are concentrated within the anterior subfields of the CBF as well as bed nucleus of the stria terminalis, amygdala, and entorhinal cortex. Galaninergic fibers hyperinnervate remaining CBF neurons in Alzheimer's disease. Because galanin inhibits the release of acetylcholine in the hippocampus, it has been suggested that the overexpression of galanin in Alzheimer's disease may downregulate the production of acetylcholine within CBF perikarya, further exacerbating cholinergic cellular dysfunction in this disorder. These observations suggest that the development of a potent galanin antagonist would be a useful step towards the successful pharmacologic treatment of Alzheimer's disease.

Acetylcholine↗

PubMed1998

Age-related declines in nigral neuronal function correlate with motor impairments in rhesus monkeys.

Although the role of dopamine dysfunction is well established in Parkinson's disease, the effect of nigrostriatal degeneration on motor performance during normal aging is less well understood. In this study, aged rhesus monkeys (25-27 years old) displayed significant impairments relative to young (3-5 years old) cohorts in motor function as assessed on a fine motor task and home cage activity. Additionally, the clinical motor function of aged monkeys was impaired relative to young monkeys as assessed on a clinical rating scale. Unbiased stereologic measurements of the substantia nigra revealed a significant age-related loss of tyrosine hydroxylase-immunoreactive (TH-ir; 50.3%) and dopamine transporter-immunoreactive (DAT-ir; 33.2%) nigral neurons. The monkeys performance on the fine motor task and on the clinical rating scale was correlated with TH-ir neuronal counts. The number of DAT-ir nigral neurons was correlated with activity and clinical rating scale scores. Our results suggest that age-related motor impairments in nonhuman primates are associated with spontaneous decreases in TH-ir and DAT-ir nigral cells. The correlation of motor deficits with the loss of TH-ir and DAT-ir nigral neurons suggests that aged nonhuman primates may provide a useful model for mimicking changes seen in human aging and early Parkinson's disease.

Aging↗

PubMed1998

m2 muscarinic acetylcholine receptor-immunoreactive neurons are not reduced within the nucleus basalis in Alzheimer's disease: relationship with cholinergic and galaninergic perikarya.

The distribution of profiles containing the m2-muscarinic acetylcholine receptor within the aged human basal forebrain and its relationship to cholinergic and noncholinerigc neurons and alterations in Alzheimer's disease (AD) was investigated by using an m2-specific monoclonal antibody (Levey et al. [1995] J. Comp. Neurol. 351:339-356). Immunocytochemistry revealed that the m2 receptor protein is expressed primarily in noncholinergic multipolar neurons (mean+/-S.E.M.; 355.7+/-15.4 microm2) located primarily outside the cholinergic nucleus basalis subfields. Dual-stained sections from the septal/diagonal band complex revealed that m2 was detected in only 14% of choline acetyltransferase-labeled neurons, whereas only 13% of m2-stained neurons colocalized choline acetyltransferase. Within the nucleus basalis, choline acetyltransferase was found in 35% of the m2-labeled neurons, whereas only 6% of choline acetyltransferase-stained perikarya were dual labeled for m2. Although we did not visualize colocalization of m2+/choline acetyltransferase-immunonegative neurons and the inhibitory neuropeptide galanin, galaninergic fibers coursed in close apposition to m2+ cells. Cell counts demonstrated that 90% of choline acetyltransferase-labeled striatal neurons expressed the m2 receptor. Despite the extensive reduction in cholinergic basal forebrain neurons, cell counts of the relative number ofm2-immunoreactive neurons within the nucleus basalis complex from aged controls and AD patients revealed that the m2 neurons are spared. Finally, our findings suggest that most m2 receptors in the cholinergic basal forebrain are located on noncholinergic structures; therefore, they are not the major source of m2 receptors in the cortex. Thus, the reduced levels of the m2 receptor seen in AD cortex probably reflect changes in other neuronal populations.

Aged↗

PubMed1998

Characterization and localization of galanin receptors in human entorhinal cortex.

The neuropeptide galanin (GAL) has a widespread distribution throughout the human cortex. The entorhinal cortex (ENT) plays a crucial role in the transfer of cortico-cortical information related to memory and displays severe degeneration in Alzheimer's disease (AD). However, very little is known about the pharmacology of the GAL receptor (GALR) in normal human ENT. Therefore, we pharmacologically visualized their distribution and characterized GALRs using in vitro receptor autoradiography and radioligand binding assays. Autoradiograms revealed intense GALR labeling, mainly in the substantia innominata, hypothalamus, the bed nucleus of the stria terminalis and within layers 2 and 4 of the ENT. Kinetic experiments showed that saturation of GALR sites by [125I]GAL (human) (hGAL) occurred within 2 h and that this binding readily reversed in the presence of a GTP analog, but not in the presence of excess unlabeled hGAL. Analysis of [125I]hGAL binding data from saturation experiments gave KD values of 98.6+/-21.6 pM, Bmax values of 52.9+/-32.4 fmol/mg protein and identified a high and low affinity state of the GALR. The presence of 5'-guanylylimidodiphosphate (GppNHp) or NaCl reduced the agonist labeling of hGALR in ENT membranes.

Adult↗

PubMed1998

Fetal nigral grafts survive and mediate clinical benefit in a patient with Parkinson's disease.

We have previously demonstrated that fetal nigral grafts can survive, reinnervate the striatum, and mediate clinically relevant recovery in a patient with Parkinson's disease (PD). Most previous autopsy cases have failed to identify meaningful numbers of viable grafted cells suggesting that differences in critical transplant variables determine graft viability. The present study evaluated the structural and functional correlates of fetal nigral transplantation in a second PD patient who received fetal nigral grafts according to our previously published transplant protocol. A 61-year-old woman with severe PD received bilateral fetal nigral grafts to the postcommissural putamen from seven donor fetuses (four right side and three left side) aged 6.5-9 weeks postconception. This patient died 19 months after surgery from a cause unrelated to the transplant surgery. Her postoperative clinical course was characterized by improved motor and activities of daily living scores during "off time," reduced "off time," and increased "on" time without dyskinesia. Positron emission tomography (PET) scans revealed a bilateral and progressive increase in fluorodopa (FD) uptake within the grafted putamen. Postmortem examination of the right hemisphere revealed large oval-shaped grafts containing more than 138,000 tyrosine-hydroxylase-immunoreactive (TH-ir) neurons. Grafted cells formed a seamless border with the host and provided dense TH-ir innervation to 78% of the host postcommissural putamen. Graft-mediated sprouting of host fibers was not observed. These data provide essential confirmation that, under appropriate transplant conditions, grafted nigral neurons can survive, reinnervate the host striatum, and provide clinical benefit to PD patients. These findings also support the concept that improved motor function and striatal FD uptake on PET after nigral grafting in PD are the result of the viability of grafted neurons and graft-derived reinnervation of the host striatum.

Brain Tissue Transplantation↗

PubMed1998

Tyrosine kinase A, galanin and nitric oxide synthase within basal forebrain neurons in the rat.

Cholinergic basal forebrain neurons appear to play a key role in cognition and attention. In rat, basal forebrain neurons express multiple proteins including the high-affinity signal transducing tyrosine kinase A receptor for nerve growth factor, the neuropeptide galanin and nitric oxide synthase, a marker for the novel neurotransmitter nitric oxide. The present study was undertaken to define the relationship between neurons expressing each of these markers within the medial septum-vertical limb of the diagonal band, horizontal limb of the diagonal band and nucleus basalis in colchicine pre-treated rats. Tyrosine kinase A-immunopositive neurons were seen throughout all subfields of the basal forebrain. In contrast, nitric oxide synthase- and galanin-immunoreactive neurons were mainly distributed within the septal-diagonal band complex. Co-localization experiments revealed that virtually all nitric oxide synthase-positive neurons (visualized by nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry) also contained tyrosine kinase A, whereas many fewer tyrosine kinase A neurons were nicotinamide adenine dinucleotide phosphate-diaphorase positive within the medial septum-vertical limb of the diagonal band. Within the horizontal limb of the diagonal band, numerous nicotinamide adenine dinucleotide phosphate-diaphorase neurons expressed tyrosine kinase A, whereas only a small number of tyrosine kinase A neurons contained nicotinamide adenine dinucleotide phosphate-diaphorase. Within the nucleus basalis very few neurons were nicotinamide adenine dinucleotide phosphate-diaphorase reactive, and a minor number contained tyrosine kinase A. Additional co-localization experiments revealed minor percentages of neurons containing nicotinamide adenine dinucleotide phosphate-diaphorase and galanin immunoreactivity within the various subfields of the basal forebrain. Within the horizontal limb of the diagonal band minor numbers of nicotinamide adenine dinucleotide phosphate-diaphorase-reactive perikarya displayed galanin. Similarly, only a few galanin-containing neurons expressed nicotinamide adenine dinucleotide phosphate-diaphorase. The existence of tyrosine kinase A, nitric oxide synthase and galanin within select neuronal subgroups of the cholinergic basal forebrain suggests that these perikarya are responsive to a complex set of chemical signals. A greater understanding of the chemical signature of the cholinergic basal forebrain neurons will provide the insight required to develop novel pharmacological approaches aimed at preventing or slowing the degenerative processes that effect these neurons in aging and pathologic disorders.

Animals↗

PubMed1997

Grafts of EGF-responsive neural stem cells derived from GFAP-hNGF transgenic mice: trophic and tropic effects in a rodent model of Huntington's disease.

The present study examined whether implants of epidermal growth factor (EGF)-responsive stems cells derived from transgenic mice in which the glial fibrillary acid protein (GFAP) promoter directs the expression of human nerve growth factor (hNGF) could prevent the degeneration of striatal neurons in a rodent model of Huntington's disease (HD). Rats received intrastriatal transplants of GFAP-hNGF stem cells or control stem cells followed 9 days later by an intrastriatal injection of quinolinic acid (QA). Nissl stains revealed large striatal lesions in rats receiving control grafts, which, on average, encompassed 12.78 mm3. The size of the lesion was significantly reduced (1.92 mm3) in rats receiving lesions and GFAP-hNGF transplants. Rats receiving QA lesions and GFAP-hNGF-secreting grafts stem cell grafts displayed a sparing of striatal neurons immunoreactive (ir) for glutamic acid decarboxylase, choline acetyltransferase, and neurons histochemically positive for nicotinamide adenosine diphosphate. Intrastriatal GFAP-hNGF-secreting implants also induced a robust sprouting of cholinergic fibers from subjacent basal forebrain neurons. The lesioned striatum in control-grafted animals displayed numerous p75 neurotrophin-ir (p75NTR) astrocytes, which enveloped host vasculature. In rats receiving GFAP-hNGF-secreting stem cell grafts, the astroglial staining pattern was absent. By using a mouse-specific probe, stem cells were identified in all animals. These data indicate that cellular delivery of hNGF by genetic modification of stem cells can prevent the degeneration of vulnerable striatal neural populations, including those destined to die in a rodent model of HD, and supports the emerging concept that this technology may be a valuable therapeutic strategy for patients suffering from this disease.

Animals↗

PubMed1997

Carrier mediated delivery of NGF: alterations in basal forebrain neurons in aged rats revealed using antibodies against low and high affinity NGF receptors.

The distribution of low and high affinity nerve growth factor (NGF) receptors was investigated in the basal forebrain during aging and NGF treatment. A peripheral administration model for NGF was utilized. NGF was conjugated to a transferrin receptor antibody (OX-26-NGF), and this conjugate was injected into the tail vein of aged Fischer 344 male rats (24 months) twice weekly for 5 weeks (equivalent to 50 microg of NGF/injection). Controls were injected with a non-conjugated mixture of OX-26 and NGF. The aged rats treated with conjugate showed a significant increase in cell size of p75- and trkA-immunoreactive neurons in the medial septal nucleus and vertical limb of the diagonal band as compared to controls. A significant increase in cell size of trkA-immunoreactive neurons was also observed in the horizontal limb of the diagonal band in rats treated with conjugate. Rats treated with conjugate also showed a significant increase in overall staining density for p75 and trkA antibodies in the medial septal nucleus as compared to controls. A significant increase in staining density of p75-immunoreactive structures was also observed in the vertical and horizontal limbs of the diagonal band. Therefore, treatment with OX-26-NGF conjugate has regional effects on both the low and high affinity NGF receptors in terms of cell body size and staining density in the basal forebrain of aged rats. The current findings support the idea that this delivery system might be useful in therapeutic approaches involving the delivery of neurotrophic factors and other large molecules into the brain.

Aging↗

PubMed1997

Connections of the hippocampal formation in humans: II. The endfolial fiber pathway.

We investigated the anatomical connections of the pyramidal neurons located within the hilar region of the dentate gyrus of the human hippocampus, neurons which do not have a rodent equivalent. The myeloarchitectural patterns of the human hippocampus indicated the presence of a distinct fiber pathway, the endfolial fiber pathway, in the stratum oriens of the hilus and field CA3. By using the fluorescent lipophilic dye DiI in formalin-fixed human hippocampal tissue, we demonstrated that this is a continuous fiber pathway between the deep hilar region and CA2. This fiber pathway did not enter the fimbria or alveus along the entire distance of the traced pathway and ran exclusively in the stratum oriens of the hilus and CA3. Tracing studies with biocytin in in vitro human hippocampal slices indicated that the hilar and CA3 pyramidal neurons contributed to this pathway. Out distally in field CA3, the long transverse fibers became short and choppy, suggesting that they were beginning to move out of the plane of the tissue slice. Numerous fibers from this pathway were seen crossing the pyramidal layer. Based on comparative studies, we propose that the endfolial fiber system is a component of the hilar Schaffer collateral system in humans. The presence of a significant Schaffer collateral system from the pyramidal neurons in the hilar region would indicate that these neurons are anatomically related to the CA3 pyramidal neurons. Therefore, we suggest the inclusion of the human hilar pyramidal neurons within Lorente de No's field CA3 and, in particular, within subfield CA3c.

Adult↗

PubMed1997

Presenilin-1 protein expression in familial and sporadic Alzheimer's disease.

Mutations of the presenilin PS1 and PS2 genes are closely linked to aggressive forms of early-onset (< 60 years) familial Alzheimer's disease. A highly specific monoclonal antibody was developed to identify and characterize the native PS1 protein. Western blot analyses revealed a predominant 32-kd immunoreactive polypeptide in a variety of samples, including PC12 cells transfected with human PS1 complementary DNA, brain biopsy specimens from demented patients, and postmortem samples of frontal neocortex from early-onset familial Alzheimer's disease cases (PS1 and PS2), late-onset sporadic Alzheimer's disease cases, and cases of other degenerative disorders. This truncated polypeptide contains the N-terminus of PS1 and appeared unchanged across cases. In 2 early-onset cases linked to missense mutations in the PS1 gene, a PS1 immunoreactive protein (approximately 49 kd) accumulated in the frontal cortex. This protein was similar in size to full-length PS1 protein present in transfected cells overexpressing PS1 complementary DNA, and in lymphocytes from an affected individual with a deletion of exon 9 of the PS1 gene, suggesting that mutations of the PS1 gene peturb the endoproteolytic processing of the protein. Immunohistochemical studies of control brains revealed that PS1 is expressed primarily in neurons, with the protein localized in the soma and dendritic processes. In contrast, PS1 showed striking localization to the neuropathology in early-onset familial Alzheimer's disease and sporadic Alzheimers' disease cases. PS1 immunoreactivity was present in the neuritic component of senile plaques as well as in neurofibrillary tangles. Localization of PS1 immunoreactivity in familial and sporadic Alzheimer's disease suggests that genetically heterogeneous forms of the disease share a common pathophysiology involving PS1 protein.

Adult↗

PubMed1997

Cellular delivery of NGF does not alter the expression of beta-amyloid immunoreactivity in young or aged nonhuman primates.

The present study determined whether grafts of nerve growth factor-producing fibroblasts alter the expression of beta-amyloid in young or aged nonhuman primates. Aged monkeys serve as an animal model which normally exhibits beta-amyloid-laden plaques. Three young adult (7-12 years of age) and three aged (24-29 years of age) rhesus monkeys received intraventricular implants of polymer-encapsulated cells that were genetically modified to secrete human recombinant nerve growth factor (NGF). Three young adult and three aged rhesus monkeys received identical treatment except that the grafted cells were not genetically modified and thus differed only by a single gene construct. Five additional aged rhesus monkeys were ungrafted and also served as controls. Three to four weeks posttransplantation, young monkeys did not display beta-amyloid-immunoreactive profiles within any CNS structure regardless of treatment. Qualitative observations revealed that aged monkeys displayed numerous beta-amyloid plaque-like structures within the amygdala and hippocampus as well as limbic and neocortices. The amount of beta-amyloid immunoreactivity (beta-amyloid load) was quantified bilaterally within the temporal neocortex of these animals. The beta-amyloid load within the temporal neocortex of aged monkeys was highly variable but did not differ across treatment groups. These data indicate that chronic short-term administration of NGF does not affect the expression of beta-amyloid in the young or the aged primate brain.

Aging↗

PubMed1997

Reduction in p140-TrkA receptor protein within the nucleus basalis and cortex in Alzheimer's disease.

It has been hypothesized that the diminished transport of nerve growth factor (NGF) seen within cholinergic basal forebrain (CBF) neurons in Alzheimer's disease (AD) results from a defect in the expression of its high-affinity trkA receptor. The present study used an anti-human trkA-specific monoclonal antibody (mAb 5C3) that recognizes the NGF docking site, combined with quantitative optical densitometry, to evaluate whether expression of the trkA protein is altered within the nucleus basalis and its cortical projection sites in AD. In normal aged humans, trkA immunoreactivity revealed a continuum of positive neurons extending throughout all CBF subfields. In addition, trkA-positive neurons were scattered throughout the olfactory tubercle and striatum. These regions also displayed intense trkA neuropil staining. Although fewer in total number, remaining CBF perikarya in AD displayed a significant decrease in trkA levels relative to aged controls. Biochemical analysis revealed a significant reduction in trkA protein within both the nucleus basalis and the frontal cortex in AD relative to aged controls. In contrast, trkA levels in the caudate nucleus were unaffected. The decrease in trkA protein in conjunction with our recent observations that the message for trkA is reduced within individual CBF neurons in AD supports the concept that defects in the production and/or utilization of the trkA receptor may be a key event mediating degeneration of NGF-responsive CBF neurons in this disease.

Aged↗