Dataset Information

Disease and Region Specificity of Granulin Immunopositivities in Alzheimer Disease and Frontotemporal Lobar Degeneration.

ABSTRACT: Heterozygous loss-of-function mutations in GRN, the progranulin gene, which result in progranulin (PGRN) protein haploinsufficiency, are a major cause of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). PGRN is composed of seven and a half repeats of a highly conserved granulin motif that is cleaved to produce the granulin peptides A-G and paragranulin. To better understand the role of PGRN and granulin (Grn) peptides in the pathogenesis of neurodegeneration, we evaluated PGRN/Grn in brains of patients with Alzheimer disease, FTLD-TDP type A with or without GRN mutations, and normal individuals, using a panel of monoclonal antibodies against Grn peptides A-G. In the neocortex, Grn peptide-specific immunostains were observed, for example, membranous Grn E immunopositivity in pyramidal neurons, and Grn C immunopositivity in ramified microglia. In the hippocampus, Grn immunopositivity in the CA1 and CA2 regions showed disease-specific changes in both neurons and microglia. Most interestingly, in FTLD-TDP type A with GRN mutations, there is a 60% decrease in the density of Grn-positive microglia in the hippocampal CA1, suggesting that haploinsufficiency of the GRN mutations also extends to PGRN expression in microglia. This study provides important insights into future studies of the pathogenesis and treatment of FTLD-TDP.

SUBMITTER: Mao Q

PROVIDER: S-EPMC5939662 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Disease and Region Specificity of Granulin Immunopositivities in Alzheimer Disease and Frontotemporal Lobar Degeneration.

Mao Qinwen Q Wang Dongyang D Li Yanqing Y Kohler Missia M Wilson Jayson J Parton Zachary Z Shmaltsuyeva Bella B Gursel Demirkan D Rademakers Rosa R Weintraub Sandra S Mesulam Marek-Marsel MM Xia Haibin H Bigio Eileen H EH

Journal of neuropathology and experimental neurology 20171101 11

Heterozygous loss-of-function mutations in GRN, the progranulin gene, which result in progranulin (PGRN) protein haploinsufficiency, are a major cause of frontotemporal lobar degeneration with TDP-43 proteinopathy (FTLD-TDP). PGRN is composed of seven and a half repeats of a highly conserved granulin motif that is cleaved to produce the granulin peptides A-G and paragranulin. To better understand the role of PGRN and granulin (Grn) peptides in the pathogenesis of neurodegeneration, we evaluated ...[more]

PMID: 29044416

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Project description:Deficits in the generation and control of saccades have been described in clinically defined frontotemporal dementia (FTD) and Alzheimer disease (AD).To determine the saccade abnormalities associated with autopsy-defined cases of frontotemporal lobar degeneration (FTLD) and of AD, because clinical FTD syndromes can correspond to a number of different underlying neuropathologic FTD and non-FTD diagnoses.An infrared eye tracker was used to record visually guided saccades to 10° targets and antisaccades in subjects with autopsy-confirmed FTD and subjects with autopsy-confirmed AD, a mean (SE) of 35.6 (10.0) months prior to death, and age-matched normal controls. Twelve subjects with FTD had an FTLD-TAR DNA-binding protein 43 pathology, 15 had an FTLD-tau pathology, and 1 subject showed an FTLD-fused in sarcoma protein pathology. Receiver operating curve statistics were used to determine the diagnostic value of the oculomotor variables. Neuroanatomical correlates of oculomotor abnormalities were investigated using voxel-based morphometry.Memory and Aging Center, Department of Neurology, University of California, San Francisco.A total of 28 subjects with autopsy-confirmed FTD, 10 subjects with autopsy-confirmed AD, and 27 age-matched normal controls.All subjects with FTD or AD were impaired relative to normal controls on the antisaccade task. However, only FTLD-tau and AD cases displayed reflexive visually guided saccade abnormalities. The AD cases displayed prominent increases in horizontal saccade latency that differentiated them from the FTD cases. Impairments in velocity and gain were most severe in individuals with progressive supranuclear palsy but were also present in other tauopathies. By using vertical and horizontal saccade velocity and gain as our measures, we were able to differentiate patients with progressive supranuclear palsy from other patients. Vertical saccade velocity was strongly correlated with dorsal midbrain volume.Decreased visually guided saccade velocity and gain are suggestive of underlying tau pathology in FTD, with vertical saccade abnormalities most diagnostic of progressive supranuclear palsy.

Project description:Frontotemporal lobar degeneration with ? pathology (FTLD-tau) is one of a group of neurodegenerative diseases that manifests with cognitive decline. Alzheimer (AD) and cerebrovascular lesions are commonly noted in the brains of most elderly individuals, begging the question as to whether (a) coexisting AD and vascular pathology or age contribute to the development of FTLD-tau disorders and vice versa and (b) FTLD-tau-like pathology can be found in non-diseased individuals. We studied brains of FTLD-tau cases exhibiting (a) argyrophilc grain disease (AGD), (b) progressive supranuclear palsy (PSP), (c) corticobasal degeneration (CBD), or (d) Pick's disease (PiD) for coexisting AD and vascular pathology for comparison with that of non-diseased individuals and AD patients. We confirmed that AGD lowered the threshold for AD pathology to cause dementia. Such an effect was not seen in PSP, CBD, or PiD. In PiD, white matter degeneration and demyelination was observed in the frontal and temporal lobes in association with small vessel disease (SVD)-related changes in white matter arteries. Age at death varied among the four types of FTLD-tau. PiD cases were youngest at death followed by CBD, PSP, and finally AGD. In 9.8% of non-diseased controls, we found grains, coiled bodies, and/or ?-positive astrocytes mimicking an AGD-like pattern. Moreover, the prevalence of FTLD-tau pathology in non-diseased individuals increased with age. In summary, this study demonstrates that age impacts of the diversity of neuropathological changes in FTLD-tau. The age-related coexistence of AD-related pathology is, thereby, associated with AGD but not with PSP, CBD, and PiD. Moreover, severe SVD and white matter demyelination is associated with PiD indicating a role of vascular copathology in this type of FTLD-tau. Finally, our finding that FTLD-tau-related pathological lesions occur in non-diseased individuals suggests that preclinical stages of FTLD-tau exist. As such, our results indicate that age, together with vascular and AD-related copathology, contributes to the morphological appearance of FTLD-tau.

Dataset Information

Disease and Region Specificity of Granulin Immunopositivities in Alzheimer Disease and Frontotemporal Lobar Degeneration.

Publications

Disease and Region Specificity of Granulin Immunopositivities in Alzheimer Disease and Frontotemporal Lobar Degeneration.

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