阻断NMDA受体可增强皮质酮对海马脑源性神经营养因子表达的抑制:cAMP反应元件结合蛋白的作用

高浓度的皮质酮可引起海马形态与功能的损伤,其中脑源性神经营养因子(brain-derived neurotrophic factor,BDNF) 表达的改变在海马形态与功能损伤中扮演重要角色。本实验的目的是观察单次皮下注射皮质酮后海马内BDNF-mRNA、前 体蛋白及成熟型蛋白表达的改变,并观察N-甲基-D-天冬氨酸(N-methyl-D-aspartate NMDA)受体阻滞剂MK801对皮质酮 作用的影响。实验结果显示,单次皮下注射皮质酮2 mg／kg,3 h后海马内BDNF mRNA、前体蛋白及成熟型蛋白的表达 均降低;MK801(0．1 mg／kg)对皮质酮的这一作用有增强效果。单独给予皮质酮或注射MK801 30 min后再给予皮质酮, 均能明显降低海马中cAMP反应元件结合蛋白(cAMP response element binding protein,CREB)的磷酸化水平,MK801与 皮质酮联用时CREB的磷酸化水平降低更为显著(与单独给予皮质酮相比,P<0．05)。实验结果提示,CREB磷酸化水平降 低可能是皮质酮引起海马BDNF表达减少的重要中间环节,阻断NMDA受体可加强皮质酮降低BDNF表达的效应。     

Reduced brain-derived neurotrophic factor is associated with a loss of serotonergic innervation in the hippocampus of aging mice

Brain-derived neurotrophic factor (BDNF) regulates monoamine neuronal growth, survival and function in development and throughout adulthood. At 18 months of age, mice with constitutive reductions in BDNF expression show decreased serotonin innervation in the hippocampus compared with age-matched wildtype mice. It is not known, however, whether age-accelerated loss of serotonergic innervation in BDNF(+/-) mice occurs in other brain regions, advances beyond 18 months or is associated with alterations in other neurotransmitter systems. In this study, immunocytochemistry was used to assess serotonergic and catecholaminergic innervation in 26-month-old BDNF(+/-) mice. Age-related loss of serotonin axons in the hippocampus was potentiated in BDNF(+/-) mice compared with wildtype mice at this late age, particularly in the CA1 subregion. By contrast, aging BDNF(+/-) mice showed increased serotonin innervation of the basomedial nucleus of the amygdala. In the noradrenergic system, BDNF(+/-) mice showed reduced numbers of cell bodies and fibers in the locus coeruleus compared with age-matched wildtype mice, whereas no changes were observed in dopaminergic innervation with respect to genotype. In vivo zero net flux microdialysis in awake mice showed a significant decrease in extracellular serotonin levels in the hippocampus in BDNF(+/-) mice at 20 months of age. Thus, reduced BDNF is associated with altered serotonergic and noradrenergic innervation in aging mice and, in particular, with accelerated loss of serotonergic innervation to the hippocampus that is manifest as a decrease in basal neurotransmission.     

The effects of chronic alcoholization on the expression of brain-derived neurotrophic factor and its receptors in the brains of mice genetically predisposed to depressive-like behavior

Brain-derived neurotropic factor (BDNF) plays an important role in mechanisms of depression. Precursor protein of this factor (proBDNF) can initiate apoptosis in the brain, while the mature form of BDNF is involved in neurogenesis. It is known that chronic alcoholization leads to the activation of apoptotic processes, neurodegeneration, brain injury, and cognitive dysfunction. In this work, we have studied the influence of long-term ethanol exposure on the proBDNF and BDNF protein levels, as well as on the expression of genes that encode these proteins in the brain structures of ASC mice with genetic predisposition to depressive-like behavior and in mice from parental nondepressive CBA strain. It was shown that chronic alcoholization results in a reduction of the BDNF level in the hippocampus and an increase in the amount of TrkB and p75 receptors in the frontal cortex of nondepressive CBA mice. At the same time, the long-term alcoholization of depressive ASC mice results in an increase of the proBDNF level in the frontal cortex and a reduction in the p75 protein level in the hippocampus. It has also been shown that, in depressive ASC mice, proBDNF and BDNF levels are significantly lower in the hippocampus and the frontal cortex compared with nondepressive CBA strain. However, no significant differences in the expression of genes encoding the studied proteins were observed. Thus, changes in the expression patterns of proBDNF, BDNF, and their receptors under the influence of alcoholization in the depressive ASC strain and nondepressive CBA strain mice are different.     

Effect of the brain-derived neurotrophic factor and the apolipoprotein E polymorphisms on disease progression in preclinical Alzheimer's disease

Genetic factors, such as apolipoprotein E (ApoE) polymorphisms, are thought to play an important role in the etiology of Alzheimer's disease (AD). Recent association studies have suggested that the Val66Met polymorphism in the brain-derived neurotrophic factor ( BDNF ) gene could play a role in the development of AD. To identify genotypic effects of the BDNF and the ApoE genes on disease progression in preclinical AD, we assessed morphological changes using serial magnetic resonance imaging during the preclinical period of AD in 35 individuals. When all subjects were analyzed as one group, progressive atrophy was noted in the limbic, paralimbic and neocortical areas. Individuals of the BDNF Val/Val genotype showed progressive atrophy in the left medial temporal areas, whereas the BDNF Met allele carriers showed additional changes in the anterior cingulate cortex (ACC), posterior cingulate cortex (PCC) and the precuneus. An interaction between the BDNF genotype and progressive morphological changes was found in the PCC. The noncarriers for the ApoE ɛ4 allele showed progressive atrophy in the bilateral medial temporal areas. In addition to changes in the medial temporal areas, ɛ4 carriers showed progressive atrophy in the PCC, ACC and precuneus. An interaction between the ApoE genotype and progressive morphological change was noted in the right medial temporal area. The present preliminary study indicates that polymorphisms of the ApoE and the BDNF genes could affect disease progression in preclinical AD and implies that the Met-BDNF polymorphism could be an additional risk factor for rapid disease progression in preclinical AD.     

Investigating the role of brain-derived neurotrophic factor in relapsing-remitting multiple sclerosis

Multiple sclerosis (MS) is a common, heterogeneous disorder of the central nervous system with a complex trait composed of both genetic and environmental factors. Recently, scientific interest has increased in defining factors that possibly contribute to brain functional plasticity; the results might be useful to assess the relationship between MS lesion burden and clinical events, as well as explaining the well-known phenotypic heterogeneity of the disease. In this study, we explored the effect of the Val66Met brain-derived neurotrophic factor (BDNF) functional polymorphism on cognitive performances and volumetric measurements obtained by magnetic resonance imaging of the brain in a selected population of relapsing-remitting MS (RRMS) patients, with relatively short disease duration and minimal clinical disability, compared to gender, age and educational-level matched healthy subjects. We found that in the RRMS group, the BDNF Met-allele was significantly associated with the lower volume of cerebral grey matter (GM) (P = 0.005). Furthermore, a significant (P = 0.013) interaction effect between 'MS-status' and the BDNF genotype was found for GM volumes, with the result that patients carrying the BDNF Met-allele showed a higher risk of developing global GM atrophy than the homozygous Val/Val. No BDNF-related impact on global neuropsychological functions resulted in either RRMS patients or controls. Our data seem to be consistent with the reported influence of BDNF in neuronal plasticity, thus suggesting that the Met-allele might have a negative prognostic effect on cortical morphometry in RRMS patients.     

脑源性神经营养因子研究进展

脑源性神经营养因子是一种小分子二聚体蛋白质,在结构上与神经生长因子相关。对中枢神经系统的多种类型神经元的生长、发育、分化、维护和再生部具有重要作用,对于治疗运动神经元病变以及神经系统迟行性疾病有显疗效。本对其细胞与分子生物学特征、生物学功能进行阐述。     

Galectin-1 induces astrocyte differentiation, which leads to production of brain-derived neurotrophic factor

Brain-derived neurotrophic factor (BDNF) is a neuroprotective polypeptide that is thought to be responsible for neuron proliferation, differentiation, and survival. An agent that enhances production of BDNF is expected to be useful for the treatment of neurodegenerative diseases. Here we report that galectin-1, a member of the family of beta-galactoside binding proteins, induces astrocyte differentiation and strongly inhibits astrocyte proliferation, and then the differentiated astrocytes greatly enhance their production of BDNF. Induction of astrocyte differentiation and BDNF production by an endogenous mammalian lectin may be a new mechanism for preventing neuronal loss after injury.     

Role for brain-derived neurotrophic factor in learning and memory

In addition to its actions on neuronal survival and differentiation, brain-derived neurotrophic factor (BDNF) has a role in the regulation of synaptic strength. Long-term potentiation, a form of synaptic plasticity, is markedly impaired in BDNF mutant mice, but the changes were restored by the re-expression of BDNF. BDNF also influences the development of patterned connections and the growth and complexity of dendrites in the cerebral cortex. These results suggest a role for BDNF in learning and memory processes, since memory acquisition is considered to involve both short-term changes in electrical properties and long-term structural alterations in synapses. Memory acquisition is associated with an increase in BDNF mRNA and TrkB receptor activation in specific brain areas. Moreover, the pharmacologic and genetic deprivation of BDNF or its receptor TrkB results in severe impairment of learning and memory in mice, rats and chicks. The effect of BDNF on learning and memory may be linked to the modulation of NMDA and non-NMDA receptor functions as well as the expression of synaptic proteins required for exocytosis. Activation of the mitogen-associated protein kinase and/or phosphatidylinositol 3-kinase signaling pathways may be involved in BDNF-dependent learning and memory formation. It is concluded that BDNF/TrkB signaling plays an important role in learning and memory.     

Down regulation of trk but not p75NTR gene expression in single cholinergic basal forebrain neurons mark the progression of Alzheimer's disease

Dysfunction of cholinergic basal forebrain (CBF) neurons of the nucleus basalis (NB) is a cardinal feature of Alzheimer's disease (AD) and correlates with cognitive decline. Survival of CBF neurons depends upon binding of nerve growth factor (NGF) with high-affinity (trkA) and low-affinity (p75(NTR)) neurotrophin receptors produced within CBF neurons. Since trkA and p75(NTR) protein levels are reduced within CBF neurons of people with mild cognitive impairment (MCI) and mild AD, trkA and/or p75(NTR) gene expression deficits may drive NB degeneration. Using single cell expression profiling methods coupled with custom-designed cDNA arrays and validation with real-time quantitative PCR (qPCR) and in situ hybridization, individual cholinergic NB neurons displayed a significant down regulation of trkA, trkB, and trkC expression during the progression of AD. An intermediate reduction was observed in MCI, with the greatest decrement in mild to moderate AD as compared to controls. Importantly, trk down regulation is associated with cognitive decline measured by the Global Cognitive Score (GCS) and the Mini-Mental State Examination (MMSE). In contrast, there is a lack of regulation of p75(NTR) expression. Thus, trk defects may be a molecular marker for the transition from no cognitive impairment (NCI) to MCI, and from MCI to frank AD.     

Mature and precursor brain-derived neurotrophic factor have individual roles in the mouse olfactory bulb

Background

Sensory deprivation induces dramatic morphological and neurochemical changes in the olfactory bulb (OB) that are largely restricted to glomerular and granule layer interneurons. Mitral cells, pyramidal-like neurons, are resistant to sensory-deprivation-induced changes and are associated with the precursor to brain-derived neurotrophic factor (proBDNF); here, we investigate its unknown function in the adult mouse OB.

Principal Findings

As determined using brain-slice electrophysiology in a whole-cell configuration, brain-derived neurotrophic factor (BDNF), but not proBDNF, increased mitral cell excitability. BDNF increased mitral cell action potential firing frequency and decreased interspike interval in response to current injection. In a separate set of experiments, intranasal delivery of neurotrophic factors to awake, adult mice was performed to induce sustained interneuron neurochemical changes. ProBDNF, but not BDNF, increased activated-caspase 3 and reduced tyrosine hydroxylase immunoreactivity in OB glomerular interneurons. In a parallel set of experiments, short-term sensory deprivation produced by unilateral naris occlusion generated an identical phenotype.

Conclusions

Our results indicate that only mature BDNF increases mitral cell excitability whereas proBDNF remains ineffective. Our demonstration that proBDNF activates an apoptotic marker in vivo is the first for any proneurotrophin and establishes a role for proBDNF in a model of neuronal plasticity.     

Secretion of brain-derived neurotrophic factor from PC12 cells in response to oxidative stress requires autocrine dopamine signaling

Expression of brain-derived neurotrophic factor (BDNF) is sensitive to changes in oxygen availability, suggesting that BDNF may be involved in adaptive responses to oxidative stress. However, it is unknown whether or not oxidative stress actually increases availability of BDNF by stimulating BDNF secretion. To approach this issue we examined BDNF release from PC12 cells, a well-established model of neurosecretion, in response to hypoxic stimuli. BDNF secretion from neuronally differentiated PC12 cells was strongly stimulated by exposure to intermittent hypoxia (IH). This response was inhibited by N-acetyl-l-cysteine, a potent scavenger of reactive oxygen species (ROS) and mimicked by exogenous ROS. IH-induced BDNF release requires activation of tetrodotoxin sensitive Na+ channels and Ca2+ influx through N- and L-type channels, as well as mobilization of internal Ca2+ stores. These results demonstrate that oxidative stress can stimulate BDNF release and that underlying mechanisms are similar to those previously described for activity-dependent BDNF secretion from neurons. Surprisingly, we also found that IH-induced secretion of BDNF was blocked by dopamine D2 receptor antagonists or by inhibition of dopamine synthesis with alpha-methyl-p-tyrosine. These data indicate that oxidative stress can stimulate BDNF release through an autocrine or paracrine loop that requires dopamine receptor activation.     

Enhancement of translation elongation in neurons by brain-derived neurotrophic factor: implications for mammalian target of rapamycin signaling

The effects and signaling mechanisms of brain-derived neurotrophic factor (BDNF) on translation elongation were investigated in cortical neurons. BDNF increased the elongation rate approximately twofold, as determined by measuring the ribosomal transit time. BDNF-accelerated elongation was inhibited by rapamycin, implicating the mammalian target of rapamycin (mTOR). To explore the mechanisms underlying these effects, we examined the protein phosphorylation cascades that lead to the activation of translation elongation in neurons. BDNF increased eukaryote elongation factor 1A (eEF1A) phosphorylation and decreased eEF2 phosphorylation. Whereas eEF2 phosphorylation levels altered by BDNF were inhibited by rapamycin, eEF1A phosphorylation was not affected by rapamycin or PD98059, a mitogen-activated protein kinase kinase (MEK) inhibitor. BDNF induced phosphorylation of eEF2 kinase (Ser366), as well as decreased its kinase activity. All these events were inhibited by rapamycin. Furthermore, mTOR siRNA, which reduced mTOR levels up to 50%, inhibited the BDNF-induced enhancement in elongation rate and decrease in eEF2 phosphorylation. These results strongly suggest that BDNF enhances translation elongation through the activation of the mTOR-eEF2 pathway.     

Induction of brain-derived neurotrophic factor by convulsant drugs in the rat brain: involvement of region-specific voltage-dependent calcium channels

A high level of hippocampal brain-derived neurotrophic factor (BDNF) in normally aged as compared with young rats suggests that it is important to maintain a considerable level of hippocampal BDNF during aging in order to keep normal hippocampal functions. To elucidate possible mechanisms of endogenous BDNF increase, changes in levels of BDNF were studied in the rat brain following systemic administration of various convulsant agents; excitotoxic glutamate agonists, NMDA, kainic acid and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA); GABA receptor antagonists, picrotoxin, pentylenetetrazole (PTZ) and lindane (gamma-hexachlorocyclohexane); and L-type voltage-dependent calcium channel agonist, BAY-K 8644. Kainic acid and AMPA, but not NMDA, caused remarkable increases in BDNF protein in the rat hippocampus and entorhinal cortex. Picrotoxin, PTZ and lindane stimulated BDNF production in the entorhinal cortex and also in the hippocampus of rats showing very severe convulsions. On the other hand, BAY-K 8644 treatment increased BDNF levels in the neocortex and entorhinal cortex. Maximal levels of BDNF protein were observed at 12--24 h, 8--16 h and 6 h following administration of kainic acid, PTZ and BAY-K 8644, respectively. Kainic acid stimulated BDNF synthesis in presynaptic hippocampal granule neurons, but not in postsynaptic neurons with its receptors, while PTZ and BAY-K 8644 produced the same effects in postsynaptic neurons in the entorhinal cortex (in granule neurons in the hippocampus) and in the whole cortex, respectively. Nifedipine inhibited almost completely BAY-K 8644, but not PTZ, effects. omega-Conotoxin GVIA and DCG-IV partially blocked kainic acid-induced enhancement of BDNF, indicating involvement of L-type and N-type voltage-dependent calcium channels, respectively. In addition, BDNF levels in the hippocampus of mice deficient in D-myo-inositol-1,4,5-triphosphate receptor gene were scarcely different from those in the same region of controls, suggesting little involvement of intracellular calcium increase through this receptor. BAY-K 8644, but not kainic acid or PTZ, stimulated the phosphorylation of cyclic AMP responsive element binding protein. Our results indicate convulsant-dependent stimulation of BDNF production and involvement of region-specific voltage-dependent calcium channels.     

Calcitonin gene-related peptide enhances release of native brain-derived neurotrophic factor from trigeminal ganglion neurons

Activity-dependent plasticity in nociceptive pathways has been implicated in pathomechanisms of chronic pain syndromes. Calcitonin gene-related peptide (CGRP), which is expressed by trigeminal nociceptors, has recently been identified as a key player in the mechanism of migraine headaches. Here we show that CGRP is coexpressed with brain-derived neurotrophic factor (BDNF) in a large subset of adult rat trigeminal ganglion neurons in vivo. Using ELISA in situ, we show that CGRP (1-1000 nM) potently enhances BDNF release from cultured trigeminal neurons. The effect of CGRP is dose-dependent and abolished by pretreatment with CGRP receptor antagonist, CGRP(8-37). Intriguingly, CGRP-mediated BDNF release, unlike BDNF release evoked by physiological patterns of electrical stimulation, is independent of extracellular calcium. Depletion of intracellular calcium stores with thapsigargin blocks the CGRP-mediated BDNF release. Using transmission electron microscopy, our study also shows that BDNF-immunoreactivity is present in dense core vesicles of unmyelinated axons and axon terminals in the subnucleus caudalis of the spinal trigeminal nucleus, the primary central target of trigeminal nociceptors. Together, these results reveal a previously unknown role for CGRP in regulating BDNF availability, and point to BDNF as a candidate mediator of trigeminal nociceptive plasticity.     

Levels of serum brain-derived neurotrophic factor in primates

Brain-derived neurotrophic factor (BDNF) has been reported to exist not only in nervous tissue but also in serum. In contrast to the wealth of knowledge regarding the various physiological functions of BDNF in the nervous system, information about possible roles in other systems is limited. To elucidate the physiological function of serum BDNF in primates, it is first necessary to establish a method to determine the levels of BDNF in serum of primates. In the present study, we established an enzyme-linked immunosorbent assay (ELISA) method which we used to measure levels of serum BDNF in non-human primates. We found that serum BDNF levels were similar among several species of primates. The present results suggest that our BDNF ELISA may be useful in measuring serum BDNF concentration as a physiological marker, and that levels of serum BDNF may be similar among primates including humans. Electronic Publication     

Polysialic acid limits choline acetyltransferase activity induced by brain-derived neurotrophic factor

Choline acetyltransferase (ChAT), the enzyme synthesizing acetylcholine, is known to be activated by brain derived neurotrophic factor (BDNF). We found that the specific removal of the carbohydrate polysialic acid (PSA) significantly increased BDNF-induced ChAT-activity in embryonic septal neurons. Using a p75 neurotrophin receptor (p75(NTR)) function-blocking antibody and K252a, a-pan tropomyosin related kinase (Trk) inhibitor, we demonstrate that BDNF-induced ChAT activity requires the stimulation of p75(NTR) and TrkB. PSA removal drastically increased radioactive iodinated ([(125)I])BDNF's maximal binding capacity (Bmax), derived from concentrations of [(125)I]BDNF ranging from 1 pM to 3.2 nM. In the presence of unlabeled nerve growth factor to prevent the binding of [(125)I]BDNF to p75(NTR) sites, the impact of PSA removal on the binding capacity of [(125)I]BDNF was greatly reduced. In conclusion, PSA limits BDNF-induced ChAT activity and BDNF-receptor interactions. BDNF-induced ChAT activity is TrkB and p75(NTR) dependent, and upon PSA removal the additional binding of BDNF to its receptors, especially p75(NTR), likely contributes to the maximal ChAT activity observed. In vivo, the ontogenetic loss of PSA in the postnatal period may allow more interactions between BDNF and its receptors to increase ChAT activity and assure the proper development of the cholinergic septal neurons.     

miR-210 inhibits cell migration and invasion by targeting the brain-derived neurotrophic factor in glioblastoma

Recently, there is increasing evidence that microRNAs are related to the development, diagnosis, treatment, and prognosis of glioblastoma. microRNA-210 (miR-210) had been identified in many human cancers, but the specific function of miR-210 remains unclear in glioblastoma. The present study mainly focused on exploring its biological role and potential molecular mechanisms in glioblastoma. We found that miR-210 expression was decreased in glioblastoma, and downregulation of miR-210 was related to worse prognosis in glioblastoma patients. In addition, miR-210 overexpression inhibited the migration and invasion of human glioblastoma cells. At the same time, we found that miR-210 directly targets the brain-derived neurotrophic factor (BDNF) and reduces BDNF expression level. Consistently, BDNF silencing had the same effects as miR-210 overexpression in glioblastoma, and upregulation of BDNF counteracted the inhibitory effect of miR-210 in glioblastoma. In conclusion, miR-210 suppressed the migration and invasion of glioblastoma cells by targeting BDNF.     

In vivo up-regulation of brain-derived neurotrophic factor in specific brain areas by chronic exposure to Delta-tetrahydrocannabinol

Cannabinoids are widely abused drugs. Here we show that chronic administration of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the active psychotropic agent in marijuana and hashish, at 1.5 mg per kg per day intraperitoneally for 7 days, increases the expression, at both mRNA and protein levels, of brain-derived neurotrophic factor (BDNF), in specific rat brain areas, notably in those involved in reward and addiction. Real-time PCR revealed a 10-fold up-regulation of BDNF mRNA in the nucleus accumbens (NAc) upon chronic Delta(9)-THC treatment, but there was no change at 3 or 24 h after a single injection. Smaller increases in mRNA levels were found in the ventral tegmental area (VTA), medial prefrontal cortex and paraventricular nucleus (PVN). Immunohistochemistry showed large increases in BDNF-stained cells in the NAc (5.5-fold), posterior VTA (4-fold) and PVN (1.7-fold), but no change was observed in the anterior VTA, hippocampus or dorsal striatum. Altogether, our study indicates that chronic exposure to Delta(9)-THC up-regulates BDNF in specific brain areas involved with reward, and provides evidence for different BDNF expression in the anterior and posterior VTA. Moreover, BDNF is known to modulate synaptic plasticity and adaptive processes underlying learning and memory, leading to long-term functional and structural modification of synaptic connections. We suggest that Delta(9)-THC up-regulation of BDNF expression has an important role in inducing the neuroadaptive processes taking place upon exposure to cannabinoids.     

Neuronal LR11 Expression Does Not Differentiate between Clinically-Defined Alzheimer's Disease and Control Brains

Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Because the pathological changes underlying this disease can begin decades prior to the onset of cognitive impairment, identifying the earliest events in the AD pathological cascade has critical implications for both the diagnosis and treatment of this disease. We previously reported that compared to autopsy confirmed healthy control brain, expression of LR11 (or SorLA) is markedly reduced in AD brain as well as in a subset of people with mild cognitive impairment (MCI), a prodromal clinical stage of AD. Recent studies of the LR11 gene SORL1 have suggested that the association between SORL1 single nucleotide polymorphisms (SNPs) and AD risk may not be universal. Therefore, we sought to confirm our earlier findings in a population chosen solely based on clinical criteria, as in most genetic studies. Quantitative immunohistochemistry was used to measure LR11 expression in 43 cases from the Religious Orders Study that were chosen based on a final pre-mortem clinical diagnosis of MCI, mild/moderate AD or no cognitive impairment (NCI). LR11 expression was highly variable in all three diagnostic groups, with no significant group differences. Low LR11 cases were identified using the lowest tertile of LR11 expression observed across all cases as a threshold. Contrary to previous reports, low LR11 expression was found in only 29% of AD cases. A similar proportion of both the MCI and NCI cases also displayed low LR11 expression. AD-associated lesions were present in the majority of cases regardless of diagnostic group, although we found no association between LR11 levels and pathological variables. These findings suggest that the relationship between LR11 expression and the development of AD may be more complicated than originally believed.