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Biomedical subjects

Ralph N Martins

Publications and source records attributed to Ralph N Martins.

At least 19 recordsLinked to original sources
PubMed2012

Clinical and biomarker changes in dominantly inherited Alzheimer's disease.

BACKGROUND: The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS: In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS: Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS: We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.).

Age of Onset↗
PubMed2004

Luteinizing hormone, a reproductive regulator that modulates the processing of amyloid-beta precursor protein and amyloid-beta deposition.

Hormonal changes associated with the dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis following menopause/andropause have been implicated in the pathogenesis of Alzheimer's disease (AD). Experimental support for this has come from studies demonstrating an increase in amyloid-beta (Abeta) deposition following ovariectomy/castration. Because sex steroids and gonadotropins are both part of the HPG feedback loop, any loss in sex steroids results in a proportionate increase in gonadotropins. To assess whether Abeta generation was due to the loss of serum 17beta-estradiol or to the up-regulation of serum gonadotropins, we treated C57Bl/6J mice with the anti-gonadotropin leuprolide acetate, which suppresses both sex steroids and gonadotropins. Leuprolide acetate treatment resulted in a 3.5-fold (p < 0.0001) and a 1.5-fold (p < 0.024) reduction in total brain Abeta1-42 and Abeta1-40 concentrations, respectively, after 8 weeks of treatment. To further explore the role of gonadotropins in promoting amyloidogenesis, M17 neuroblastoma cells were treated with the gonadotropin luteinizing hormone (LH) at concentrations equivalent to early adulthood (10 mIU/ml) or post-menopause/andropause (30 mIU/ml). LH did not alter amyloid-beta precursor protein (AbetaPP) expression but did alter AbetaPP processing toward the amyloidogenic pathway as evidenced by increased secretion and insolubility of Abeta, decreased alphaAbetaPP secretion, and increased AbetaPP-C99 levels. These results suggest the marked increases in serum LH following menopause/andropause as a physiologically relevant signal that could promote Abeta secretion and deposition in the aging brain. Suppression of the age-related increase in serum gonadotropins using anti-gonadotropin agents may represent a novel therapeutic strategy for AD.

Aging↗
PubMed2004

Amyloid-beta-induced toxicity of primary neurons is dependent upon differentiation-associated increases in tau and cyclin-dependent kinase 5 expression.

It has previously been reported that amyloid-beta (Abeta) peptide is neurotrophic to undifferentiated but neurotoxic to differentiated primary neurons. The underlying reasons for this differential effect is not understood. Recently, the toxicity of Abeta to neurons was shown to be dependent upon the activation of cyclin-dependent kinase 5 (Cdk5), thought to promote tau phosphorylation that leads to cytoskeletal disruption, morphological degeneration and apoptosis. Here we report that Cdk5, tau, and phosphorylated-tau (P-tau) are expressed at very low levels in undifferentiated primary neurons, but that the expression of Cdk5 and tau and the phosphorylation of tau increase markedly between 4 and 8 days of differentiation in vitro. Tau expression decreased after this time, as did the level of P-tau, to low levels by 17 days. Abeta induced tau phosphorylation of neurons only after >or= 4 days of differentiation, a time that coincides with the onset of Abeta toxicity. Blocking tau expression (and therefore tau phosphorylation) with an antisense oligonucleotide completely blocked Abeta toxicity of differentiated primary neurons, thereby confirming that tau was essential for mediating Abeta toxicity. Our results demonstrate that differentiation-associated changes in tau and Cdk-5 modulate the toxicity of Abeta and explain the opposite responses of differentiated and undifferentiated neurons to Abeta. Our results predict that only cells containing appreciable levels of tau are susceptible to Abeta-induced toxicity and may explain why Abeta is more toxic to neurons compared with other cell types.

Amyloid beta-Peptides↗
PubMed2003

Increased levels of apolipoprotein E in the frontal cortex of subjects with schizophrenia.

BACKGROUND: It is unclear whether altered expression of a specific isoform of apolipoprotein E (apoE) is associated with the pathology of schizophrenia. METHODS: To address whether apoE may be involved in the pathology of schizophrenia, we measured the genotypic and allelic frequency of polymorphisms in its gene and transcriptional regulatory region in DNA from Brodmann's area (BA) 9 obtained postmortem from schizophrenic and control subjects as well as its levels in the same tissue using Western blot analysis. RESULTS: The genotypic or allelic frequencies of any polymorphism studied did not vary between diagnostic cohorts. There was a significant increase in the levels of apoE protein in BA 9 from the schizophrenic subjects (Mean +/- SEM: 270 +/- 8.3 vs. 238 +/- 7.1 ng apoE/mg protein, p =.008) and a decrease in tissue from an analogous cortical region from rats treated with haloperidol compared with vehicle-treated animals (50 +/- 6.4 vs. 116 +/- 9.2 ng apoE/mg protein; p =.0002). CONCLUSIONS: These data support the hypothesis that increased levels of apoE may be associated with the pathology of schizophrenia and that antipsychotic drugs decrease apoE levels as part of their therapeutic actions.

Adult↗
PubMed2003

XB51 isoforms mediate Alzheimer's beta-amyloid peptide production by X11L (X11-like protein)-dependent and -independent mechanisms.

XB51 (derived from X11-like binding protein of clone number 51) was isolated by yeast two-hybrid cDNA screening using the N-terminal domain of X11L (X11-like protein) as a bait. X11L is a neuron-specific adaptor protein that is known to down-regulate APP (beta-amyloid precursor protein) metabolism by associating with the cytoplasmic domain of APP, but the detailed mechanisms are still unknown. Thus the X11L-associated protein XB51 is believed to regulate APP metabolism by modifying X11L function through its interaction with X11L. Here we report that the hXB51 (human XB51 ) gene can yield two transcripts, one with exon 9 spliced out (resulting in the hXB51beta isoform) and the other containing exon 9 (yielding the hXB51alpha isoform). hXB51alpha binds to X11L to form a tripartite complex composed of hXB51alpha, X11L and APP. Complex-formation results in blocking X11L's suppression of Abeta (beta-amyloid) generation from APP. hXB51beta associates with X11L and inhibits its interaction with APP. However, hXB51beta suppresses Abeta generation and secretion in an X11L-independent manner. Thus the hXB51 isoforms regulate Abeta generation differently, either enhancing it by modifying the association of X11L with APP or suppressing it in an X11L-independent manner. These observations advance our understanding of the molecular mechanisms regulating intracellular Abeta production and the pathogenesis of Alzheimer's disease.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Apolipoprotein D levels are elevated in prefrontal cortex of subjects with Alzheimer's disease: no relation to apolipoprotein E expression or genotype.

BACKGROUND: Apolipoprotein E (apoE) has been implicated in the pathology of AD ever since inheritance of the epsilon4 allele was shown to be an important risk factor for the development of AD. Apolipoprotein D (apoD) is elevated in association with several central nervous system disorders, including Alzheimer's disease (AD), and has been proposed to be an especially robust marker for brain regions specifically affected by particular neuropathologies. Progressive cognitive decline is the core clinical feature of AD and is associated with disturbances in the prefrontal cortex. METHODS: We measured apoD levels in prefrontal cortex samples obtained postmortem from 20 autopsy-confirmed AD subjects and 40 control subjects. RESULTS: Enzyme-linked immunosorbent assay analysis revealed a significant increase in apoD expression in AD subjects compared with control subjects (.218+/-.029 microg/mg protein vs.117+/-.011 microg/mg protein; p=0003). There was no significant difference in apoD expression between early-onset and late-onset Alzheimer's subjects. Apolipoprotein D expression levels were not correlated with apoE levels, nor were they correlated with inheritance of the APOE epsilon4 allele. CONCLUSIONS: These findings suggest that apoD may be related to the cognitive decline observed in AD patients and that apoD and apoE likely play different roles in the pathogenesis of AD.

Aged↗
PubMed2003

Reduction of inclusion body pathology in ApoE-deficient mice fed a combination of antioxidants.

Clinical studies have shown that the antioxidant vitamin E can slow the progression of Alzheimer's disease (AD). Other antioxidants reported to affect cognitive function include ginkgo biloba, vitamin C, and lipoic acid. To examine the effects of combination antioxidant therapy (CAT) on longevity and neuropathology in mice, we supplemented the diet of ApoE-deficient mice with vitamin E, ginkgo biloba, pycnogenol, and ascorbyl palmitate. ApoE-deficient mice normally exhibit increased numbers of PAS-positive inclusion bodies with aging. However, supplementation with CAT resulted in a significant increase in life span and a marked reduction of inclusion body histopathology in the hippocampus. In addition, while untreated apoE-deficient mice exhibited increased levels of TUNEL staining, a marker of DNA fragmentation, supplementation with CAT resulted in a significant reduction in the levels of TUNEL staining. These findings suggest that oxidative mechanisms, perhaps related to neuronal apoptosis, are integral to inclusion body formation in aging mice. The association between the reduced number of apoptotic cells and the reduction in inclusion bodies may explain in part the increased longevity of mice fed CAT, and supports the contention that the combined actions of selected antioxidants may be therapeutically effective against neurodegenerative diseases.

Animal Feed↗
PubMed2003

Amyloid-beta: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-beta.

Although much maligned, the amyloid-beta (Abeta) protein has been shown to possess a number of trophic properties that emanate from the protein's ability to bind Cu, Fe and Zn. Abeta belongs to a group of proteins that capture redox metal ions (even under mildly acidotic conditions), thereby preventing them from participating in redox cycling with other ligands. The coordination of Cu appears to be crucial for Abeta's own antioxidant activity that has been demonstrated both in vitro as well as in the brain, cerebrospinal fluid and plasma. The chelation of Cu by Abeta would therefore be predicted to dampen oxidative stress in the mildly acidotic and oxidative environment that accompanies acute brain trauma and Alzheimer's disease (AD). Given that oxidative stress promotes Abeta generation, the formation of diffuse amyloid plaques is likely to be a compensatory response to remove reactive oxygen species. This review weighs up the evidence supporting both the trophic and toxic properties of Abeta, and while evidence for direct Abeta neurotoxicity in vivo is scarce, we postulate that the product of Abeta's antioxidant activity, hydrogen peroxide (H(2)O(2)), is likely to mediate toxicity as the levels of this oxidant rise with the accumulation of Abeta in the AD brain. We propose that metal ion chelators, antioxidants, antiinflammatories and amyloid-lowering drugs that target the reduction of H(2)O(2) and/or Abeta generation may be efficacious in decreasing neurotoxicity. However, given the antioxidant activity of Abeta, we suggest that the excessive removal of Abeta may prevent adequate chelation of metal ions and removal of O(2)(-z.ccirf;), leading to enhanced, rather than reduced, neuronal oxidative stress.

Alzheimer Disease↗
PubMed2003

Two novel presenilin-1 mutations (Y256S and Q222H) are associated with early-onset Alzheimer's disease.

Mutations in the gene encoding presenilin 1 (PS-1) account for 50% of early-onset familial Alzheimer's disease (EOFAD) cases. In this study, we identified two missense mutations in the coding sequence of the presenilin (PS-1) gene in two EOFAD pedigrees. AD was confirmed in one pedigree by autopsy. Mutation analysis of PCR products amplified from genomic DNA templates showed two novel PS-1 mutations resulting in Gln222His and Tyr256Ser. The two novel mutations are located within predicted transmembrane domains five (TM-5) and six (TM-6), respectively, and are associated with very early ages of onset. The Tyr256Ser is associated with one of the youngest age of AD onset, 25 years, which is consistent with a drastic change in function of the altered PS-1 protein. A morphometric analysis of the cortical degenerative changes of the Tyr256Ser case, showed severe involvement of the primary motor cortex, which correlated well with the pyramidal changes, including tetraspasticity. Immunoblot analysis showed the Tyr256Ser case had the greatest expression of Abeta(1-40) and Abeta(1-42), which was confirmed by ELISA, compared to other PS-1 mutant FAD cases and age-matched controls and, thus, contributes to the severity of the disease pathology.

Adult↗
PubMed2003

Can testosterone replacement decrease the memory problem of old age?

The world is rapidly ageing. It is against this backdrop that there are increasing incidences of dementia reported worldwide, with Alzheimer's disease (AD) being the most common form of dementia in the elderly. It is estimated that AD affects almost 4 million people in the US, and costs the US economy more than 65 million dollars annually. There is currently no cure for AD but various therapeutic agents have been employed in attempting to slow down the progression of the illness, one of which is oestrogen. Over the last decades, scientists have focused mainly on the roles of oestrogen in the prevention and treatment of AD. Newer evidences suggested that testosterone might also be involved in the pathogenesis of AD. Although the exact mechanisms on how androgen might affect AD are still largely unknown, it is known that testosterone can act directly via androgen receptor-dependent mechanisms or indirectly by converting to oestrogen to exert this effect. Clinical trials need to be conducted to ascertain the putative role of androgen replacement in Alzheimer's disease.

Aging↗
PubMed2003

Expanding the association between the APOE gene and the risk of Alzheimer's disease: possible roles for APOE promoter polymorphisms and alterations in APOE transcription.

Alzheimer's disease (AD) is the most commonly diagnosed form of dementia in the elderly. Predominantly this disease is sporadic in nature with only a small percentage of patients exhibiting a familial trait. Early-onset AD may be explained by single gene defects; however, most AD cases are late onset (> 65 years) and, although there is no known definite cause for this form of the disease, there are several known risk factors. Of these, the epsilon4 allele of the apolipoprotein E (apoE) gene (APOE) is a major risk factor. The epsilon4 allele of APOE is one of three (epsilon2 epsilon3 and epsilon4) common alleles generated by cysteine/arginine substitutions at two polymorphic sites. The possession of the epsilon 4 allele is recognized as the most common identifiable genetic risk factor for late-onset AD across most populations. Unlike the pathogenic mutations in the amyloid precursor or those in the presenilins, APOE epsilon4 alleles increase the risk for AD but do not guarantee disease, even when present in homozygosity. In addition to the cysteine/arginine polymorphisms at the epsilon2/epsilon3/epsilon4 locus, polymorphisms within the proximal promoter of the APOE gene may lead to increased apoE levels by altering transcription of the APOE gene. Here we review the genetic and biochemical evidence supporting the hypothesis that regulation of apoE protein levels may contribute to the risk of AD, distinct from the well known polymorphisms at the epsilon2/epsilon3/epsilon4 locus.

Alzheimer Disease↗
PubMed2003

Mutations in the tau gene that cause an increase in three repeat tau and frontotemporal dementia.

The majority of cases with frontotemporal dementia (FTD) have no tau deposition in the brain, yet mutations in the tau gene lead to a similar clinical phenotype with insoluble tau depositing in neuropathological lesions. We report two tau gene mutations at positions +19 and +29, in the intronic sequences immediately following the stem loop structure in exon 10, which segregate with FTD. Exon-trapping experiments showed that these gene mutations alter the splicing out of exon 10 and produce an increase in tau isoforms with three microtubule binding domains (three repeat tau). Mutagenesis experiments demonstrated that the +19 mutation was responsible for the increase in three repeat tau, possibly by altering an intron silencer modulator sequence element found at this region of the gene. Microtubule binding experiments revealed a significant decrease in microtubule assembly with increasing amounts of three and decreasing amounts of four repeat tau. Brain autopsy was available in one case. Analysis of the type of soluble tau isoforms revealed an increase in three repeat tau and an absence of tau isoforms with exon 3 inserts. No insoluble tau was isolated in the tissue fractions, consistent with the absence of tau-positive histopathology. There was also an increase in tau degradation products suggestive of increased proteolysis. This increase in tau breakdown products was associated with TUNEL- and activated caspase-3-positive neurons identified histologically. These studies show that increases in soluble three repeat tau can be responsible for FTD in cases with tau gene mutations in the intronic region immediately adjacent to the stem loop in exon 10. These cases of FTD have tau isoforms (without exon 3 inserts) that do not form abnormal aggregates and appear more prone to proteolysis. The increase in tau proteolysis was associated with increased evidence of apoptosis. This mechanism of neurodegeneration may be more applicable to the majority of FTD cases, which do not accumulate insoluble tau deposits.

Alternative Splicing↗
PubMed2002

Elevated luteinizing hormone expression colocalizes with neurons vulnerable to Alzheimer's disease pathology.

In individuals with Alzheimer's disease (AD), there is a two-fold elevation in the serum concentrations of the gonadotropins, luteinizing hormone (LH), and follicle stimulating hormone compared to age-matched controls. Whether this plays a role in disease pathogenesis is unclear. Nonetheless, gonadotropins are known to cross the blood brain barrier and the highest density of gonadotropin receptors in the brain are found within the hippocampus. We report for the first time the localization of LH in the cytoplasm of pyramidal neurons. In addition, we find a significant increase in LH in the cytoplasm of pyramidal neurons and neurofibrillary tangles of AD brain compared to age-matched control brain. Whereas the functional consequences of increased neuronal LH are unknown, it is notable that LH is primarily localized to those neurons that are known to be vulnerable to Alzheimer's disease-related neurodegeneration. Elevated serum and cortical neuron levels of LH, coupled with the decline in sex steroid production, could play important roles in the pathogenesis of AD.

Aged↗
PubMed2002

Intraneuronal advanced glycation endproducts in presenilin-1 Alzheimer's disease.

The most frequently mutated gene resulting in dominantly inherited Alzheimer's disease is presenilin-1. We have used antibodies against advanced glycation endproducts (AGE) in brain tissue sections of four patients with three different presenilin I mutations. Accumulation of intracellular AGE was observed in 75-95% of pyramidal neurons in patients with presenilin-1 mutations, far exceeding the percentage of presenilin-1-, tau- or ubiquitin-positive neurons. This high level of AGE-modified proteins in vulnerable neurons is most likely explained by higher levels of their precursors (reactive (di)carbonyl products) or a slower turnover of the participating proteins. These conditions of carbonyl stress may contribute to increased neuronal dysfunction and vulnerability leading to the early disease onset.

Adult↗
PubMed2002

Transition metal chelator therapy--a potential treatment for Alzheimer's disease?

A defining feature of Alzheimer's disease (AD) pathology is the presence of amyloid beta known as A-beta (Abeta) within neuritic plaques of the hippocampus and neocortex of the brain. While early in vitro studies suggested that Abeta could itself be toxic to neuronal cells, recent studies have indicated that this peptide has both neurotoxic and neuroprotective properties that are modulated by the binding of transition metal ions. Transition metal ion binding was shown to modulate Abeta solubility as well as its hydrogen peroxide production, thereby providing explanations for both its trophic and toxic properties. These findings lead to the suggestion that interference with this interaction may reverse the neurotoxic properties of Abeta. More recently, in vivo and in vitro studies into the effects of transition metal chelator treatments on Abeta solubilisation and neurological function have been published. Such studies have yielded promising results, however the potential side effects of many such metal chelators may prove too great for clinical use. It is widely agreed that the ideal chelator for such interdiction would act only on those transition metals that complex with Abeta, and only at metal ion binding sites that contribute to Abeta aggregation and reactive oxygen species generation. The efficacy of metal chelators in reducing Abeta load in transgenic mouse brains demonstrates that this approach has considerable merit as a research tool and as a stimulus to develop second generation agents that can selectively prevent transition metals from binding to the Abeta peptide itself without perturbing the action of other important metal requiring biomolecules in the brain.

Alzheimer Disease↗
PubMed2002

Senile plaque composition and posttranslational modification of amyloid-beta peptide and associated proteins.

Amyloid deposits are primarily composed of the amyloid-beta protein, although other proteins (and metal ions) also have been colocalized to these lesions. The pattern of oxidative modifications in amyloid plaques is very different to that associated with neurofibrillary tangles and neuronal cell bodies, likely reflecting the different composition of these structures, accessibility of oxidants, the generation of oxidants in and around these structures and the intrinsic antioxidant defense systems to protect these structures. Future studies directed at understanding Abeta interactions with other amyloid components, the role of oxidative modifications in stabilizing amyloid deposits and the determination of protease cleavage sites on Abeta may provide mechanistic insights regarding both amyloid formation and removal.

Amyloid beta-Peptides↗
PubMed2002

Altered glycosylation of acetylcholinesterase in APP (SW) Tg2576 transgenic mice occurs prior to amyloid plaque deposition.

Previous studies have shown that a minor glycoform of acetylcholinesterase (AChE) is increased in Alzheimer's disease brain and cerebrospinal fluid. This glycoform can be distinguished from other AChE species by its lack of binding to concanavalin A (Con A). In this study, the temporal relationship between AChE glycosylation and Abeta deposition was examined in Tg2576 mice. There was a significant (p < 0.05) difference in AChE glycosylation in Tg2576 mice compared with age-matched background strain control mice at 4 months of age. This difference in glycosylation was also observed in 8- and 12-month-old Tg2576 mice. In contrast, Abeta plaques were only seen in the Tg2576 mice at 12 months of age, and were not detected at 4 and 8 months of age. Soluble human-sequence Abeta was detected as early as 4 months of age in the transgenic mice. The altered AChE glycosylation was due to an increase in a minor AChE isoform, which did not bind Con A, similar to that previously observed to be increased in Alzheimer's disease brain and cerebrospinal fluid. The results demonstrate that in transgenic mice altered AChE glycosylation is associated with very early events in the development of AD-like pathology. The study supports the possibility that glycosylation may also be a useful biomarker of AD.

Acetylcholinesterase↗