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1.  A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity 
Acta Neuropathologica  2014;127(5):667-683.
Intracellular inclusions composed of hyperphosphorylated filamentous tau are a hallmark of Alzheimer’s disease, progressive supranuclear palsy, Pick’s disease and other sporadic neurodegenerative tauopathies. Recent in vitro and in vivo studies have shown that tau aggregates do not only seed further tau aggregation within neurons, but can also spread to neighbouring cells and functionally connected brain regions. This process is referred to as ‘tau propagation’ and may explain the stereotypic progression of tau pathology in the brains of Alzheimer’s disease patients. Here, we describe a novel in vivo model of tau propagation using human P301S tau transgenic mice infused unilaterally with brain extract containing tau aggregates. Infusion-related neurofibrillary tangle pathology was first observed 2 weeks post-infusion and increased in a stereotypic, time-dependent manner. Contralateral and anterior/posterior spread of tau pathology was also evident in nuclei with strong synaptic connections (efferent and afferent) to the site of infusion, indicating that spread was dependent on synaptic connectivity rather than spatial proximity. This notion was further supported by infusion-related tau pathology in white matter tracts that interconnect these regions. The rapid and robust propagation of tau pathology in this model will be valuable for both basic research and the drug discovery process.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-014-1254-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s00401-014-1254-6
PMCID: PMC4252866  PMID: 24531916
Tau; Aggregation; Propagation; Prion; Transgenic mouse line; Human P301S tau
2.  Increase in tau tyrosine phosphorylation correlates with the formation of tau aggregates 
Tauopathies are neurodegenerative disorders characterized by aberrant intracellular aggregation of hyperphosphorylated tau. It has been shown that aggregated tau is phosphorylated at serine, threonine, and tyrosine residues. However, the occurrence of tyrosine phosphorylation on tau proteins at different states of tau aggregation has not been shown. In this report, we utilized the tauopathy mouse model JNPL3 that expresses human 0N4R tau isoform bearing the missense P301L mutation to study the occurrence of tau tyrosine phosphorylation in the course of the development of tau aggregation. These mice develop behavioral and motor deficits and form sarkosyl-insoluble hyperphosphorylated tau in an age-dependent manner. Mass spectrometry analyses of immunopurified brain tau proteins from JNPL3 and Alzheimer’s disease affected individual uncovered novel tau tyrosine-phosphorylated sites. Further studies demonstrated that the abundance of tyrosine-phosphorylated tau increases in an age-dependent manner in JNPL3 mice. Tyrosine-phosphorylated tau was detected in both soluble and sarkosyl-insoluble preparations derived from brain and spinal cord, and localized in neurons containing aggregated tau. The phosphorylation of tyrosine residues in tau appeared to occur along with that of serine and threonine residues and was not detectable in non-transgenic littermates and transgenic mice expressing 0N4R wild-type human tau. The results suggest that tyrosine phosphorylation is as important as phosphorylation of other residues in tauopathy.
doi:10.1016/j.molbrainres.2005.04.015
PMCID: PMC3677942  PMID: 15913839
Tau; Tyrosine phosphorylation; Tauopathy; Transgenic mice
3.  Evidence for an association between KIBRA and late-onset Alzheimer’s disease 
Neurobiology of aging  2008;31(6):901-909.
We recently reported evidence for an association between the individual variation in normal human episodic memory and a common variant of the KIBRA gene, KIBRA rs17070145 (T-allele). Since memory impairment is a cardinal clinical feature of Alzheimer’s disease (AD), we investigated the possibility of an association between the KIBRA gene and AD using data from neuronal gene expression, brain imaging studies, and genetic association tests. KIBRA was significantly over-expressed and 3 of its 4 known binding partners under-expressed in AD-affected hippocampal, posterior cingulate and temporal cortex regions (p<0.010, corrected) in a study of laser capture microdissected neurons. Using positron emission tomography in a cohort of cognitively normal, late-middle-aged persons genotyped for KIBRA rs17070145, KIBRA T non-carriers exhibited lower glucose metabolism than did carriers in posterior cingulate and precuneus brain regions (P<0.001, uncorrected). Lastly, non-carriers of the KIBRA rs17070145 T-allele had increased risk of late-onset AD in an association study of 702 neuropathologically verified expired subjects (p=0.034; OR=1.29) and in a combined analysis of 1026 additional living and expired subjects (p=0.039; OR=1.26). Our findings suggest that KIBRA is associated with both individual variation in normal episodic memory and predisposition to AD.
doi:10.1016/j.neurobiolaging.2008.07.014
PMCID: PMC2913703  PMID: 18789830
genetics; imaging; expression profiling; memory
4.  Voxel-based morphometry in frontotemporal lobar degeneration with ubiquitin-positive inclusions with and without progranulin mutations 
Archives of neurology  2007;64(3):371-376.
Background
Mutations in the progranulin gene (PGRN) have recently been identified as a cause of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) in some families.
Objective
To determine whether there is a difference in the patterns of atrophy in cases with FTLD-U with and without a mutation in PGRN.
Design
Case control study
Setting
Brain bank of a tertiary care medical center
Patients
All subjects that had screened positive for mutations in PGRN and had a volumetric MRI were identified (n=8, PGRN (+)). Subjects were then matched by clinical diagnosis to a group of eight subjects with a pathological diagnosis of FTLD-U that had screened negative for mutations in PGRN (PGRN (−)). All subjects were then age and gender-matched to a control subject.
Main outcome Measures
Voxel-based morphometry was used to assess the patterns of grey matter atrophy in the PGRN (+) and (−) groups compared to controls, and compared to each other.
Results
The PGRN (+) group showed a widespread and severe pattern of grey matter loss predominantly affecting the frontal, temporal and parietal lobes. In comparison, the PGRN (−) group showed a less severe pattern of loss restricted mainly to the temporal and frontal lobes. On direct comparison the PGRN (+) group showed greater loss in the frontal and parietal lobes compared to the PGRN (−) group.
Conclusions
This study suggests that PGRN mutations may be associated with a specific and severe pattern of cerebral atrophy in subjects with FTLD-U.
doi:10.1001/archneur.64.3.371
PMCID: PMC2752412  PMID: 17353379
Frontotemporal dementia; Voxel-based morphometry; Ubiquitin; Dentate; Progranulin
5.  Early Onset Alzheimer’s Disease with Spastic Paraparesis, Dysarthria and Seizures and N135S Mutation in PSEN1 
Objective
Early onset familial Alzheimer’s disease (EOFAD) can be caused by mutations in genes for amyloid precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2). There is considerable phenotypic variability in EOFAD, including some patients with spastic paraparesis. The objective is to describe clinical and neuropathologic features of a family with a PSEN1 mutation that has been reported previously, without autopsy confirmation, in a single Greek family whose affected members presented with memory loss in their thirties, as well as variable limb spasticity and seizures.
Methods
We prospectively evaluated two children (son and daughter) with EOFAD and reviewed medical records on their mother. Archival material from the autopsy of the mother was reviewed and postmortem studies were performed on the brain of the daughter.
Results
All three individuals in this family had disease onset in their thirties, with cognitive deficits in multiple domains, including memory, language and attention, as well as less common features such as spastic dysarthria, limb spasticity and seizures. At autopsy both the mother and her daughter had pathologic findings of AD, as well as histological evidence of corticospinal tract degeneration. Genetic studies revealed a mutation in PSEN1 leading to an asparagine to serine substitution at amino acid residue 135 (N135S) in presenilin-1.
Conclusions
This is the first description of neuropathologic findings in EOFAD due to N135S PSEN1 mutation. The clinical phenotype was remarkable for spastic dysarthria, limb spasticity and seizures, in addition to more typical features of EOFAD.
doi:10.1097/WAD.0b013e3181732399
PMCID: PMC2750842  PMID: 18580586
Alzheimer disease; Genetics; Neuropathology; Presenilin; Spasticity
6.  Whole genome association analysis shows that ACE is a risk factor for Alzheimer's disease and fails to replicate most candidates from Meta-analysis 
For late onset Alzheimer's disease (LOAD), the only confirmed, genetic association is with the apolipoprotein E (APOE) locus on chromosome 19. Meta-analysis is often employed to sort the true associations from the false positives. LOAD research has the advantage of a continuously updated meta-analysis of candidate gene association studies in the web-based AlzGene database. The top 30 AlzGene loci on May 1st, 2007 were investigated in our whole genome association data set consisting of 1411 LOAD cases and neuropathoiogicaiiy verified controls genotyped at 312,316 SNPs using the Affymetrix 500K Mapping Platform. Of the 30 “top AlzGenes", 32 SNPs in 24 genes had odds ratios (OR) whose 95% confidence intervals that did not include 1. Of these 32 SNPs, six were part of the Affymetrix 500K Mapping panel and another ten had proxies on the Affymetrix array that had >80% power to detect an association with α=0.001. Two of these 16 SNPs showed significant association with LOAD in our sample series. One was rs4420638 at the APOE locus (uncorrected p-value=4.58E-37) and the other was rs4293, located in the angiotensin converting enzyme (ACE) locus (uncorrected p-value=0.014). Since this result was nominally significant, but did not survive multiple testing correction for 16 independent tests, this association at rs4293 was verified in a geographically distinct German cohort (p-value=0.03). We present the results of our ACE replication aiongwith a discussion of the statistical limitations of multiple test corrections in whole genome studies.
PMCID: PMC3076748  PMID: 21537449
Late-onset Alzheimer disease; single nucleotide polymorphism; genome-wide association study; meta-analysis; ACE
7.  TDP-43 IMMUNOREACTIVITY IN HIPPOCAMPAL SCLEROSIS AND ALZHEIMER'S DISEASE 
Annals of neurology  2007;61(5):435-445.
Goal
This study aimed to determine the frequency of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) in the setting of hippocampal sclerosis (HpScl) and Alzheimer's disease (AD) using immunohistochemistry for TAR DNA binding protein 43 (TDP-43), a putative marker for FTLD-U.
Methods
Initially, 21 cases of HpScl associated with a variety of other pathologic processes and 74 cases of AD were screened for FTLD-U with TDP-43 immunohistochemistry. A confirmation study was performed on 93 additional AD cases. Specificity of TDP-43 antibodies was assessed using double immunolabeling confocal microscopy, immunoelectron microscopy and biochemistry.
Results
TDP-43 immunoreactivity was detected in 71% of HpScl and 23% of AD cases. Double immunostaining of AD cases for TDP-43 and phospho-tau showed that the TDP-43 immunoreactive inclusions were usually distinct from neurofibrillary tangles. At the ultrastructural level TDP-43 immunoreactivity in AD was associated with granular and filamentous cytosolic material and only occasionally associated with tau filaments. Western blots of AD cases revealed a band that migrated at a higher molecular weight than normal TDP-43 that was not present in AD cases without TDP-43 immunoreactivity.
Interpretation
The present results suggest that as many as 20% of AD cases and more than 70% of HpScl cases have pathology similar to that found in FTLD-U. Whether this represents concomitant FTLD-U or is analogous to colocalization of α-synuclein and tau in AD, reflecting a propensity for co-deposition of abnormal protein conformers, remains to be determined.
doi:10.1002/ana.21154
PMCID: PMC2677204  PMID: 17469117
Alzheimer's disease; biochemistry; electron microscopy; frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U); hippocampal sclerosis; immunohistochemistry; TAR DNA binding protein 43 (TDP-43)
8.  GAB2 Alleles Modify Alzheimer’s Risk in APOE ε4 Carriers 
Neuron  2007;54(5):713-720.
SUMMARY
The apolipoprotein E (APOE) ε4 allele is the best established genetic risk factor for late-onset Alzheimer’s disease (LOAD). We conducted genome-wide surveys of 502,627 single-nucleotide polymorphisms (SNPs) to characterize and confirm other LOAD susceptibility genes. In ε4 carriers from neuropathologically verified discovery, neuropathologically verified replication, and clinically characterized replication cohorts of 1411 cases and controls, LOAD was associated with six SNPs from the GRB-associated binding protein 2 (GAB2) gene and a common haplotype encompassing the entire GAB2 gene. SNP rs2373115 (p = 9 × 10−11) was associated with an odds ratio of 4.06 (confidence interval 2.81–14.69), which interacts with APOE ε4 to further modify risk. GAB2 was overexpressed in pathologically vulnerable neurons; the Gab2 protein was detected in neurons, tangle-bearing neurons, and dystrophic neuritis; and interference with GAB2 gene expression increased tau phosphorylation. Our findings suggest that GAB2 modifies LOAD risk in APOE ε4 carriers and influences Alzheimer’s neuropathology.
doi:10.1016/j.neuron.2007.05.022
PMCID: PMC2587162  PMID: 17553421
9.  Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia 
Human Molecular Genetics  2008;17(23):3631-3642.
Loss-of-function mutations in progranulin (GRN) cause ubiquitin- and TAR DNA-binding protein 43 (TDP-43)-positive frontotemporal dementia (FTLD-U), a progressive neurodegenerative disease affecting ∼10% of early-onset dementia patients. Here we expand the role of GRN in FTLD-U and demonstrate that a common genetic variant (rs5848), located in the 3′-untranslated region (UTR) of GRN in a binding-site for miR-659, is a major susceptibility factor for FTLD-U. In a series of pathologically confirmed FTLD-U patients without GRN mutations, we show that carriers homozygous for the T-allele of rs5848 have a 3.2-fold increased risk to develop FTLD-U compared with homozygous C-allele carriers (95% CI: 1.50–6.73). We further demonstrate that miR-659 can regulate GRN expression in vitro, with miR-659 binding more efficiently to the high risk T-allele of rs5848 resulting in augmented translational inhibition of GRN. A significant reduction in GRN protein was observed in homozygous T-allele carriers in vivo, through biochemical and immunohistochemical methods, mimicking the effect of heterozygous loss-of-function GRN mutations. In support of these findings, the neuropathology of homozygous rs5848 T-allele carriers frequently resembled the pathological FTLD-U subtype of GRN mutation carriers. We suggest that the expression of GRN is regulated by miRNAs and that common genetic variability in a miRNA binding-site can significantly increase the risk for FTLD-U. Translational regulation by miRNAs may represent a common mechanism underlying complex neurodegenerative disorders.
doi:10.1093/hmg/ddn257
PMCID: PMC2581433  PMID: 18723524
10.  APOE ε4 lowers age at onset and is a high risk factor for Alzheimer's disease; A case control study from central Norway 
BMC Neurology  2008;8:9.
Background
The objective of this study was to analyze factors influencing the risk and timing of Alzheimer's disease (AD) in central Norway. The APOE ε4 allele is the only consistently identified risk factor for late onset Alzheimer's disease (LOAD). We have described the allele frequencies of the apolipoprotein E gene (APOE) in a large population of patients with AD compared to the frequencies in a cognitively-normal control group, and estimated the effect of the APOE ε4 allele on the risk and the age at onset of AD in this population.
Methods
376 patients diagnosed with AD and 561 cognitively-normal control individuals with no known first degree relatives with dementia were genotyped for the APOE alleles. Allele frequencies and genotypes in patients and control individuals were compared. Odds Ratio for developing AD in different genotypes was calculated.
Results
Odds Ratio (OR) for developing AD was significantly increased in carriers of the APOE ε4 allele compared to individuals with the APOE ε3/ε3 genotype. Individuals carrying APOE ε4/ε4 had OR of 12.9 for developing AD, while carriers of APOE ε2/ε4 and APOE ε3/ε4 had OR of 3.2 and 4.2 respectively. The effect of the APOE ε4 allele was weaker with increasing age. Carrying the APOE ε2 allele showed no significant protective effect against AD and did not influence age at onset of the disease. Onset in LOAD patients was significantly reduced in a dose dependent manner from 78.4 years in patients without the APOE ε4 allele, to 75.3 in carriers of one APOE ε4 allele and 72.9 in carriers of two APOE ε4 alleles. Age at onset in early onset AD (EOAD) was not influenced by APOE ε4 alleles.
Conclusion
APOE ε4 is a very strong risk factor for AD in the population of central Norway, and lowers age at onset of LOAD significantly.
doi:10.1186/1471-2377-8-9
PMCID: PMC2375917  PMID: 18416843
11.  Progranulin in frontotemporal lobar degeneration and neuroinflammation 
Progranulin (PGRN) is a pleiotropic protein that has gained the attention of the neuroscience community with recent discoveries of mutations in the gene for PGRN that cause frontotemporal lobar degeneration (FTLD). Pathogenic mutations in PGRN result in null alleles, and the disease is likely the result of haploinsufficiency. Little is known about the normal function of PGRN in the central nervous system apart from a role in brain development. It is expressed by microglia and neurons. In the periphery, PGRN is involved in wound repair and inflammation. High PGRN expression has been associated with more aggressive growth of various tumors. The properties of full length PGRN are distinct from those of proteolytically derived peptides, referred to as granulins (GRNs). While PGRN has trophic properties, GRNs are more akin to inflammatory mediators such as cytokines. Loss of the neurotrophic properties of PGRN may play a role in selective neuronal degeneration in FTLD, but neuroinflammation may also be important. Gene expression studies suggest that PGRN is up-regulated in a variety of neuroinflammatory conditions, and increased PGRN expression by microglia may play a pivotal role in the response to brain injury, neuroinflammation and neurodegeneration.
doi:10.1186/1742-2094-4-7
PMCID: PMC1805428  PMID: 17291356
12.  Analysis of IFT74 as a candidate gene for chromosome 9p-linked ALS-FTD 
BMC Neurology  2006;6:44.
Background
A new locus for amyotrophic lateral sclerosis – frontotemporal dementia (ALS-FTD) has recently been ascribed to chromosome 9p.
Methods
We identified chromosome 9p segregating haplotypes within two families with ALS-FTD (F476 and F2) and undertook mutational screening of candidate genes within this locus.
Results
Candidate gene sequencing at this locus revealed the presence of a disease segregating stop mutation (Q342X) in the intraflagellar transport 74 (IFT74) gene in family 476 (F476), but no mutation was detected within IFT74 in family 2 (F2). While neither family was sufficiently informative to definitively implicate or exclude IFT74 mutations as a cause of chromosome 9-linked ALS-FTD, the nature of the mutation observed within F476 (predicted to truncate the protein by 258 amino acids) led us to sequence the open reading frame of this gene in a large number of ALS and FTD cases (n = 420). An additional sequence variant (G58D) was found in a case of sporadic semantic dementia. I55L sequence variants were found in three other unrelated affected individuals, but this was also found in a single individual among 800 Human Diversity Gene Panel samples.
Conclusion
Confirmation of the pathogenicity of IFT74 sequence variants will require screening of other chromosome 9p-linked families.
doi:10.1186/1471-2377-6-44
PMCID: PMC1764752  PMID: 17166276

Results 1-12 (12)