Biomedical subjects

John Q Trojanowski

Publications and source records attributed to John Q Trojanowski.

At least 19 recordsLinked to original sources

PubMed2018

Sex-specific genetic predictors of Alzheimer's disease biomarkers.

Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = - 0.03, p = 4.25 × 10-8; β = 0.03, p = 3.97 × 10-8) than males (β = - 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10-10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.

Aged, 80 and over↗

PubMed2006

The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts.

Previously we have shown that the H1c haplotype on the background of the H1 clade of haplotypes at the MAPT locus is associated with increased risk for progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Alzheimer's disease (AD). Here we replicated the association with AD in an additional autopsy confirmed series. We show that this haplotype increases both the expression of total MAPT transcript as well as specifically increasing the proportion of 4 microtubule binding repeat containing transcripts. We discuss these findings both in terms of the problems facing the dissection of the etiologies of complex traits and the pathogenesis of the tauopathies.

Age of Onset↗

PubMed2006

Biochemical and pathological characterization of frontotemporal dementia due to a Leu266Val mutation in microtubule-associated protein tau in an African American individual.

Frontotemporal dementia (FTD) is a clinically heterogeneous disorder characterized by alterations in language and/or behavior, often in association with Parkinsonism or motor neuron disease. A familial form of FTD is associated with mutations in the microtubule-associated protein tau (MAPT) gene. We report here on the clinical, neuroimaging, cerebral spinal fluid biomarker, genetic, biochemical and postmortem neuropathological analyses of a case of familial FTD with a Leu266Val MAPT mutation which results in a very early age of onset and a rapid course of disease. This is also the first reported case of any MAPT mutation in an individual of African American ethnicity.

Adult↗

PubMed2006

Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.

Amino Acid Sequence↗

PubMed2006

Mechanisms of Parkinson's disease linked to pathological alpha-synuclein: new targets for drug discovery.

Classic Parkinson's disease (PD) is characterized by fibrillar alpha-synuclein inclusions known as Lewy bodies in the substantia nigra, which are associated with nigrostriatal degeneration. However, alpha-synuclein pathologies accumulate throughout the CNS in areas that also undergo progressive neurodegeneration, leading to dementia and other behavioral impairments in addition to parkinsonism. Although mutations in the alpha-synuclein gene only cause Lewy body PD in rare families, and although there are multiple other, albeit rare, genetic causes of familial parkinsonism, sporadic Lewy body PD is the most common movement disorder, and insights into mechanisms underlying alpha-synuclein-mediated neurodegeneration provide novel targets for the discovery of disease-modifying therapies for PD and related neurodegenerative alpha-synucleinopathies.

Animals↗

PubMed2006

Beta-synuclein modulates alpha-synuclein neurotoxicity by reducing alpha-synuclein protein expression.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by fibrillar aggregates of alpha-synuclein in characteristic inclusions known as "Lewy bodies". As mutations altering alpha-synuclein structure or increasing alpha-synuclein expression level can cause familial forms of PD or related Lewy body disorders, alpha-synuclein is believed to play a central role in the process of neuron toxicity, degeneration and death in "synucleinopathies". beta-synuclein is closely related to alpha-synuclein and has been shown to inhibit alpha-synuclein aggregation and ameliorate alpha-synuclein neurotoxicity. We generated beta-synuclein transgenic mice and observed a marked reduction in alpha-synuclein protein expression in the cortex of mice over-expressing beta-synuclein. This reduction in alpha-synuclein protein expression was not accompanied by decreases in alpha-synuclein mRNA expression. Using the prion protein promoter alpha-synuclein A53T mouse model of PD, we demonstrated that over-expression of beta-synuclein could retard the progression of impaired motor performance, reduce alpha-synuclein aggregation and extend survival in doubly transgenic mice. We attributed the amelioration of alpha-synuclein neurotoxicity in such bigenic mice to the ability of beta-synuclein to reduce alpha-synuclein protein expression based upon I(125) autoradiography quantification. Our findings indicate that increased expression of beta-synuclein protein results in a reduction of alpha-synuclein protein expression. As increased expression of alpha-synuclein may cause or contribute to PD pathogenesis in sporadic and familial forms of disease, this observation has important implications for the development of therapies for PD.

Animals↗

PubMed2006

Characterization of Abeta11-40/42 peptide deposition in Alzheimer's disease and young Down's syndrome brains: implication of N-terminally truncated Abeta species in the pathogenesis of Alzheimer's disease.

Senile plaques (SPs), one of two defining lesions of Alzheimer's disease (AD), are composed of a mixture of full-length Abeta1-40/42, and N- or C-terminally truncated Abeta peptides, including Abeta11-40/42. Sequential proteolysis of amyloid precursor protein (APP) by beta- and gamma-secretases produces Abeta1-40/42, but beta-site APP-cleaving enzyme 1 (BACE1), the major beta-secretase, also generates Abeta11-40/42, and BACE1 overexpression in cultured cells results primarily in secretion of Abeta11-40/42. The ratio of Abeta11-40/42 to Abeta1-40/42 depends on the ratio of BACE1 to APP, and Abeta11-40/42 can be generated from both full-length APP and its carboxy-terminal fragment (C99). Here, we investigated the role of Abeta11-40/42 in the pathogenesis of AD and Down's syndrome (DS) brains. We demonstrated significant amount of Abeta11-42 in DS brains by Western blots. While pyroAbeta11-42-modified Abeta species existed predominantly in mature SP cores in AD brain sections, both unmodified free Abeta11-40 and pyro-modified Abeta11-40 are detected in vascular amyloid deposits by immunohistochemistry. Using novel ELISAs for quantifying free Abeta11-40/42 and pyroAbeta11-40/42, we showed that insoluble Abeta11-42 predominated in extracts of AD and DS brains. This is the first systematic study of Abeta11-40/42 in neurodegenerative Abeta amyloidosis implicating Abeta11-40/42 in SP formation of AD and DS brains. The detection of Abeta11-42 in young DS brain suggests an early role for this N-terminally truncated Abeta peptide in the pathogenesis of SPs in AD and DS.

Adolescent↗

PubMed2006

Characterization of tau pathologies in gray and white matter of Guam parkinsonism-dementia complex.

Guam parkinsonism-dementia complex (PDC) is a neurodegenerative tauopathy in ethnic Chamorro residents of the Mariana Islands that manifests clinically with parkinsonism as well as dementia and is characterized neuropathologically by prominent cortical neuron loss in association with extensive telencephalic neurofibrillary tau pathology. To further characterize cortical gray and white matter tau, alpha-synuclein and lipid peroxidation pathologies in Guam PDC, we examined the brains of 17 Chamorro PDC and control subjects using biochemical and immunohistological techniques. We observed insoluble tau pathology in both gray and white matter of PDC and Guam control cases, with frontal and temporal lobes being most severely affected. Using phosphorylation dependent anti-tau antibodies, abundant tau inclusions were detected by immunohistochemistry in both neuronal and glial cells of the neocortex, while less alpha-synuclein pathology was observed in more limited brain regions. Further, in sharp contrast to Alzheimer's disease (AD), levels of the lipid peroxidation product 8, 12-iso-iPF(2alpha)-VI isoprostane were not elevated in Guam PDC brains relative to controls. Thus, although the tau pathologies of Guam PDC share similarities with AD, the composite Guam PDC neuropathology profile of tau, alpha-synuclein and 8, 12-iso-iPF(2alpha)-VI isoprostane reported here more closely resembles that seen in other tauopathies including frontotemporal dementias (FTDs), which may imply that Guam PDC and FTD tauopathies share underlying mechanisms of neurodegeneration.

Aged↗

PubMed2006

Impaired glutamate transport in a mouse model of tau pathology in astrocytes.

Filamentous tau inclusions in neurons and glia are neuropathological hallmarks of tauopathies. The discovery of microtubule-associated protein tau gene mutations that are pathogenic for a heterogenous group of neurodegenerative disorders, called frontotemporal dementia and parkinsonism linked to chromosome-17 (FTDP-17), directly implicate tau abnormalities in the onset/progression of disease. Although the role of tau pathology in neurons in disease pathogenesis is well accepted, the contribution of glial pathology is essentially unknown. We recently generated a transgenic (Tg) mouse model of tau pathology in astrocytes by expressing the human tau protein under the control of the glial fibrillary acidic protein (GFAP) promoter. Both wild-type and FTDP-17 mutant GFAP/tau Tg animals manifest an age-dependent accumulation of tau inclusions in astrocytes that resembles the pathology observed in human tauopathies. We further demonstrate that both strains of Tg mice manifest compromised motor function that correlates with altered expression of the glial glutamate-aspartate transporter and occurs before the development of tau pathology. Subsequently, the Tg mice manifest additional deficits in neuromuscular strength that correlates with reduced expression of glutamate transporter-1 (GLT-1) and occurs concurrent with tau inclusion pathology. Reduced GLT-1 expression was associated with a progressive decrease in sodium-dependent glutamate transport capacity. Reductions in GLT-1 expression were also observed in corticobasal degeneration, a tauopathy with prominent pathology in astrocytes. Less robust changes were observed in Alzheimer's disease in which neuronal tau pathology predominates. Thus, these Tg mice recapitulate features of astrocytic pathology observed in tauopathies and implicate a role for altered astrocyte function in the pathogenesis of these disorders.

Amino Acid Substitution↗

PubMed2006

Biochemical and pathological characterization of Lrrk2.

OBJECTIVE: Mutations in leucine-rich repeat kinase 2 (LRRK2) recently have been identified as the most common genetic cause of late-onset sporadic and familial Parkinson's disease (PD). The studies herein explore the biological and pathological properties of Lrrk2. METHODS: Genetic analysis was performed to identify autopsied patients with the most common Lrrk2 mutation (G2019S). Using an antibody specific to Lrrk2, the biochemical and immunocytochemical distribution of Lrrk2 was assessed. RESULTS: Three patients with the G2019S Lrrk2 mutation were identified. Two patients demonstrated classic PD with Lewy bodies, although concurrent pathological changes consistent with Alzheimer's disease were also present in one of these individuals. The third patient was characterized by parkinsonism without Lewy bodies but demonstrated dystrophic neurites in the substantia nigra intensely stained for Lrrk2. Lrrk2 accumulations were unique to this patient and Lrrk2 was not detected in other types of pathological inclusions. Biochemical analysis showed that Lrrk2 is predominantly a soluble approximately 250 kDa cytoplasmic protein expressed throughout the brain but also in many other organs. INTERPRETATION: The reasons for the selective predisposition of patients with mutations in LRRK2 to develop parkinsonism remains unclear, but Lrrk2 mutations may prime select neuronal populations to cellular insults that can lead to aberrant protein aggregation.

Adult↗

PubMed2006

Frontotemporal dementia: clinicopathological correlations.

OBJECTIVE: Frontotemporal lobar degeneration (FTLD) is characterized by impairments in social, behavioral, and/or language function, but postmortem studies indicate that multiple neuropathological entities lead to FTLD. This study assessed whether specific clinical features predict the underlying pathology. METHODS: A clinicopathological correlation was performed on 90 consecutive patients with a pathological diagnosis of frontotemporal dementia and was compared with an additional 24 cases accrued during the same time period with a clinical diagnosis of FTLD, but with pathology not typically associated with frontotemporal dementia. RESULTS: Postmortem examination showed multiple pathologies including tauopathies (46%), FTLD with ubiquitin-positive inclusions (29%), and Alzheimer's disease (17%). The pathological groups manifested some distinct demographic, clinical, and neuropsychological features, although these attributes showed only a statistical association with the underlying pathology. FTLD with ubiquitin-positive inclusions was more likely to present with both social and language dysfunction, and motor neuron disease was more likely to emerge in these patients. Tauopathies were more commonly associated with an extrapyramidal disorder. Alzheimer's disease was associated with relatively greater deficits in memory and executive function. INTERPRETATION: Clinical and neuropsychological features contribute to delineating the spectrum of pathology underlying a patient diagnosed with FTLD, but biomarkers are needed that, together with the clinical phenotype, can predict the underlying neuropathology.

Adult↗

PubMed2006

Unexpected abundance of pathological tau in progressive supranuclear palsy white matter.

OBJECTIVE: To investigate whether biochemical insoluble tau with 4 (4R) and/or 3 (3R) microtubule-binding repeats accumulate in white as well as gray matter in progressive supranuclear palsy (PSP), a neurodegenerative tauopathy. METHODS: To assess tau pathology in PSP white matter, we combined Western blot (WB) and immunohistochemical methods to analyze 23 autopsy-confirmed PSP brains. RESULTS: WBs showed an unexpected abundance of insoluble tau in white and gray matter of PSP brains, but biochemical tau pathology in white matter was not correlated with immunohistochemistry using the same panel of epitope-specific anti-tau antibodies used for WB. Despite heterogeneity in the representation of pathological 3R and 4R tau isoforms in cortical versus subcortical regions, biochemically detectable white matter tau pathology is a constant feature of PSP. INTERPRETATION: These studies show additional similarities between PSP and corticobasal degeneration, but unlike corticobasal degeneration, more abundant white matter tau pathology in PSP is detectable by WB than by immunohistochemistry. The differential detection of abnormal tau by biochemistry versus microscopy in PSP may reflect distinct pathological mechanisms, and elucidation of these processes will augment efforts to develop better strategies for the diagnosis and treatment of PSP and related neurodegenerative tauopathies.

Aged↗

PubMed2006

In vivo measurement of plaque burden in a mouse model of Alzheimer's disease.

PURPOSE: To demonstrate an MRI method for directly visualizing amyloid-beta (Abeta) plaques in the APP/PS1 transgenic (tg) mouse brain in vivo, and show that T1rho relaxation rate increases progressively with Alzheimer's disease (AD)-related pathology in the tg mouse brain. MATERIALS AND METHODS: We obtained in vivo MR images of a mouse model of AD (APP/PS1) that overexpresses human amyloid precursor protein, and measured T1rho via quantitative relaxometric maps. RESULTS: A significant decrease in T1rho was observed in the cortex and hippocampus of 12- and 18-month-old animals compared to their age-matched controls. There was also a correlation between changes in T1rho and the age of the animals. CONCLUSION: T1rho relaxometry may be a sensitive method for noninvasively determining AD-related pathology in APP/PS1 mice.

Alzheimer Disease↗

PubMed2006

Partial deficit of pantothenate kinase 2 catalytic activity in a case of tremor-predominant neurodegeneration with brain iron accumulation.

We describe an atypical case of pantothenate kinase-associated neurodegeneration (PKAN) in which slowly progressive arm tremor was the predominant symptom beginning at the age of 25, with late-onset dystonia and dysarthria developing at the age of 50. Compound heterozygous mutations resulting in missense amino acid substitutions G521R and I529V were identified in the pantothenate kinase (PANK2) gene. We demonstrate that while the G521R mutation results in an unstable and inactive protein, the previously unreported I529V substitution has no apparent effect on the stability or catalytic activity of PanK2. The phenotype that results from this combination of mutations suggests that atypical presentations of PKAN may arise from partial deficits in PanK2 catalytic activity.

Arginine↗

PubMed2006

Convergence of heat shock protein 90 with ubiquitin in filamentous alpha-synuclein inclusions of alpha-synucleinopathies.

Heat shock proteins (Hsps) facilitate refolding of denatured polypeptides, but there is limited understanding about their roles in neurodegenerative diseases characterized by misfolded proteins. Because Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy are alpha-synucleinopathies characterized by filamentous alpha-synuclein (alpha-syn) inclusions, we assessed which Hsps might be implicated in these disorders by examining human brain samples, transgenic mouse models, and cell culture systems. Light and electron microscopic multiple-label immunohistochemistry showed Hsp90 was the predominant Hsp examined that co-localized with alpha-syn in Lewy bodies, Lewy neurites, and glial cell inclusions and that Hsp90 co-localized with alpha-syn filaments of Lewy bodies in PD. Hsp90 levels were most predominantly increased in PD brains, which correlated with increased levels of insoluble alpha-syn. These alterations in Hsp90 were recapitulated in a transgenic mouse model of PD-like alpha-syn pathologies. Cell culture studies also revealed that alpha-syn co-immunoprecipitated preferentially with Hsp90 and Hsc70 relative to other Hsps, and exposure of cells to proteasome inhibitors resulted in increased levels of Hsp90. These data implicate predominantly Hsp90 in the formation of alpha-syn inclusions in PD and related alpha-synucleinopathies.

Adult↗

PubMed2006

Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies.

Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) is a common neuropathological subtype of frontotemporal dementia. Although this subtype of frontotemporal dementia is defined by the presence of ubiquitin-positive but tau- and alpha-synuclein-negative inclusions, it is unclear whether all cases of FTLD-U have the same underlying pathogenesis. Examination of tissue sections from FTLD-U brains stained with anti-ubiquitin antibodies revealed heterogeneity in the morphological characteristics of pathological inclusions among subsets of cases. Three types of FTLD-U were delineated based on morphology and distribution of ubiquitin-positive inclusions. To address the hypothesis that FTLD-U is pathologically heterogeneous, novel monoclonal antibodies (mAbs) were generated by immunization of mice with high molecular mass (Mr > 250 kd) insoluble material prepared by biochemical fractionation of FTLD-U brains. Novel mAbs were identified that immunolabeled all of the ubiquitin-positive inclusions in one subset of FTLD-U cases, whereas other mAbs stained the ubiquitin-positive inclusions in a second subset of cases. These novel mAbs did not stain inclusions in other neurodegenerative disorders, including tauopathies and alpha-synucleinopathies. Therefore, ubiquitin immunohistochemistry and the immunostaining properties of the novel mAbs generated here suggest that FTLD-U is pathologically heterogeneous. Identification of the disease proteins recognized by these mAbs will further advance understanding of molecular substrates of FTLD-U neurodegenerative pathways.

Aged↗

PubMed2006

Progress from Alzheimer's tangles to pathological tau points towards more effective therapies now.

The landmark description of neurofibrillary tangles (NFTs) and senile plaques as the pathological hallmarks of an unusual form of dementia 100 years ago by Alois Alzheimer launched the quest to understand a neurodegenerative disorder that now has become a scourge in the 21st Century due to the unprecedented increase in human life expectancy since 1900. Indeed, while there are many benefits to individuals and society as a whole that will accrue from the remarkable gains in longevity since 1900, the risk of developing Alzheimer's disease (AD) increases exponentially with advancing age beyond the 7th decade of life. Hence, the prevalence of AD will rise inexorably in the coming decades unless effective interventions are developed to delay the onset or progression of AD. Widespread international recognition of the urgency of this problem has accelerated research to discover meaningful therapies for AD, and growing evidence implicates impairments of axonal transport in mechanisms underlying AD due to pathological alterations in tau, the building block proteins of NFTs. This brief review summarizes insights into mechanisms whereby pathological alterations in tau impair axonal transport resulting in neurodegeneration and how these insights are being exploited now to develop novel therapeutic interventions for the treatment of AD.

Alzheimer Disease↗

PubMed2005

Targeting amyloid-beta peptide (Abeta) oligomers by passive immunization with a conformation-selective monoclonal antibody improves learning and memory in Abeta precursor protein (APP) transgenic mice.

Passive immunization of murine models of Alzheimer disease amyloidosis reduces amyloid-beta peptide (Abeta) levels and improves cognitive function. To specifically address the role of Abeta oligomers in learning and memory, we generated a novel monoclonal antibody, NAB61, that preferentially recognizes a conformational epitope present in dimeric, small oligomeric, and higher order Abeta structures but not full-length amyloid-beta precursor protein or C-terminal amyloid-beta precursor protein fragments. NAB61 also recognized a subset of brain Abeta deposits, preferentially mature senile plaques, and amyloid angiopathy. Using NAB61 as immunotherapy, we showed that aged Tg2576 transgenic mice treated with NAB61 displayed significant improvements in spatial learning and memory relative to control mice. These data implicated Abeta oligomers as a pathologic substrate for cognitive decline in Alzheimer disease.

Alzheimer Disease↗