Gene-based association study of genes linked to hippocampal sclerosis of aging neuropathology: GRN, TMEM106B, ABCC9, and KCNMB2

Katsumata, Yuriko; Nelson, Peter T.; Ellingson, Sally R.; Fardo, David W.

doi:10.1016/j.neurobiolaging.2017.01.003

Cited by 22 publications

(35 citation statements)

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“…It is also possible that sex could influence the findings, since men at this age are a minority of the population and power is therefore limited to test for sex differences. Findings by Nelson et al were not adjusted for sex , but given that the analyses by Katsumata et al were adjusted , this explanation is likely to be insufficient. A mechanistic link between LATE‐NC + HS and ABCC9 variation is unclear, and this study did not replicate the previous results.…”

Section: Discussionmentioning

confidence: 99%

“…Progranulin may act as a potential neurotrophic factor whose loss of function may cause neurodegeneration in FTLD‐TDP or other related diseases, and lead to the development of TDP‐43‐positive pathology in LATE‐NC + HS . Progranulin expression may have effects on cleavage and distribution of TDP‐43 . Notably, the polymorphic rs5848 site in the 3'‐untranslated region of GRN , which is associated with variations in progranulin levels and increased risk of LATE‐NC + HS, is also part of a binding site for microRNA miR‐659 .…”

Section: Discussionmentioning

confidence: 99%

“…Each SNP was analyzed using an additive mode of inheritance (number of risk alleles, ie, 0, 1, or 2). ABCC9 rs704178 was furthermore analyzed using a recessive mode of inheritance (2 risk alleles = 1; 0 otherwise), as this has previously been shown to be appropriate (8,14,16…”

Section: Statistical Approachmentioning

confidence: 99%

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Putative risk alleles for LATE‐NC with hippocampal sclerosis in population‐representative autopsy cohorts

et al. 2019

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Limbic‐predominant age‐related TAR‐DNA‐binding protein‐43 (TDP‐43) encephalopathy with hippocampal sclerosis pathology (LATE‐NC + HS) is a neurodegenerative disorder characterized by severe hippocampal CA1 neuron loss and TDP‐43‐pathology, leading to cognitive dysfunction and dementia. Polymorphisms in GRN, TMEM106B and ABCC9 are proposed as LATE‐NC + HS risk factors in brain bank collections. To replicate these results in independent population‐representative cohorts, hippocampal sections from brains donated to three such studies (Cambridge City over 75‐Cohort [CC75C], Cognitive Function and Ageing Study [CFAS], and Vantaa 85+ Study) were stained with hematoxylin–eosin (n = 744) and anti‐pTDP‐43 (n = 713), and evaluated for LATE‐NC + HS and TDP‐43 pathology. Single nucleotide polymorphism genotypes in GRN rs5848, TMEM106B rs1990622 and ABCC9 rs704178 were determined. LATE‐NC + HS (n = 58) was significantly associated with the GRN rs5848 genotype (χ2(2) = 20.61, P < 0.001) and T‐allele (χ2(1) = 21.04, P < 0.001), and TMEM106B rs1990622 genotype (Fisher's exact test, P < 0.001) and A‐allele (χ2(1) = 25.75, P < 0.001). No differences in ABCC9 rs704178 genotype or allele frequency were found between LATE‐NC + HS and non‐LATE‐NC + HS neuropathology cases. Dentate gyrus TDP‐43 pathology associated with GRN and TMEM106B variations, but the association with TMEM106B nullified when LATE‐NC + HS cases were excluded. Our results indicate that GRN and TMEM106B are associated with severe loss of CA1 neurons in the aging brain, while ABCC9 was not confirmed as a genetic risk factor for LATE‐NC + HS. The association between TMEM106B and LATE‐NC + HS may be independent of dentate TDP‐43 pathology.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Putative risk alleles for LATE‐NC with hippocampal sclerosis in population‐representative autopsy cohorts

et al. 2019

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“…To address those SNPs, we used assays for proxy SNPs that are in very close (>.98 r 2 and >.99 D') linkage disequilibrium in human (including European) populations: for rs73069071 (in SLOC1A2/IAPP), rs12301085 was assayed, and for rs9637454 (in KCNMB2), rs12496790 was assayed. For the ABCC9 gene variant, we assessed rs704180, since it has been demonstrated to be associated with HS-Aging pathology (Katsumata et al, 2017;Nelson et al, 2014;Nelson et al, 2015b). Notably, the nearby ABCC9 SNP rs4148651 was found to be an eQTL for SLCO1C1 (Nelson et al, 2016a).…”

Section: Genetic (Snp) Assaysmentioning

confidence: 99%

TDP-43 proteinopathy in aging: Associations with risk-associated gene variants and with brain parenchymal thyroid hormone levels

Nelson

Gal

Wang

et al. 2019

Neurobiology of Disease

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TDP-43 proteinopathy is very common among the elderly (affecting at least 25% in individuals over 85 years of age) and is associated with substantial cognitive impairment. Risk factors implicated in age-related TDP-43 proteinopathy include commonly inherited gene variants, comorbid Alzheimer's disease pathology, and thyroid hormone dysfunction. To test parameters that are associated with aging-related TDP-43 pathology, we performed exploratory analyses of pathologic, genetic, and biochemical data derived from research volunteers in the University of Kentucky Alzheimer's Disease Center autopsy cohort (n=136 subjects). Digital pathologic methods were used to discriminate and quantify both neuritic and intracytoplasmic pathology in the hippocampal formation. Overall, 46.4% of the cases were positive for TDP-43 intracellular inclusions, which is consistent with results in other prior community-based cohorts. The pathologies were correlated with hippocampal sclerosis of aging (HS-Aging) linked genotypes. We also assayed brain parenchymal thyroid hormone (triiodothyronine [T3] and thyroxine [T4]) levels. In cases with SLCO1A2/IAPP or ABCC9 risk associated genotypes, the T3/T4 ratio tended to be reduced (p=0.051 using 2-tailed statistical test), and in cases with low T3/T4 ratios (bottom quintile), there was a higher likelihood of HS-Aging pathology (p=0.025 using 2-tailed statistical test). This is intriguing because the SLCO1A2/IAPP and ABCC9 risk associated genotypes have been associated with altered expression of the astrocytic thyroid hormone receptor (product of the nearby gene SLCO1C1). These data indicate that dysregulation of thyroid hormone signaling may play a role in TDP-43 proteinopathy.

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“…More recent research showed that β2 subunit activity can regulate suprachiasmatic nucleus rhythm and circadian behavior by inactivation of BK currents ( Whitt et al, 2016 ). Also, a SNP (RS9637454) of Kcnmb2 was reported to be strongly associated with hippocampal sclerosis, a comorbid neuropathological feature of AD ( Gibson et al, 2014 ; Katsumata et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Kcnmb2 in Dorsal CA1 of Offspring Mice Rescues Hippocampal Dysfunction Caused by a Methyl Donor-Rich Paternal Diet

Guo

et al. 2018

Front. Cell. Neurosci.

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BK channels are known regulators of neuronal excitability, synaptic plasticity, and memory. Our previous study showed that a paternal methyl donor-rich diet reduced the expression of Kcnmb2, which encodes BK channel subunit beta 2, and caused memory deficits in offspring mice. To explore the underlying cellular mechanisms, we investigated the intrinsic and synaptic properties of CA1 pyramidal neurons of the F1 offspring mice whose fathers were fed with either a methyl donor-rich diet (MD) or regular control diet (CD) for 6 weeks before mating. Whole-cell patch-clamp recordings of CA1 pyramidal neurons revealed a decrease in intrinsic excitability and reduced frequency of inhibitory post-synaptic currents in MD F1 mice compared to the CD F1 controls. AAV-based overexpression of Kcnmb2 in dorsal CA1 ameliorated changes in neuronal excitability, synaptic transmission, and plasticity in MD F1 mice. Our findings thus indicate that a transient paternal exposure to a methyl donor-rich diet prior to mating alters Kcnmb2-sensitive hippocampal functions in offspring animals.

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Gene-based association study of genes linked to hippocampal sclerosis of aging neuropathology: GRN, TMEM106B, ABCC9, and KCNMB2

Cited by 22 publications

References 60 publications

Putative risk alleles for LATE‐NC with hippocampal sclerosis in population‐representative autopsy cohorts

Putative risk alleles for LATE‐NC with hippocampal sclerosis in population‐representative autopsy cohorts

TDP-43 proteinopathy in aging: Associations with risk-associated gene variants and with brain parenchymal thyroid hormone levels

Overexpression of Kcnmb2 in Dorsal CA1 of Offspring Mice Rescues Hippocampal Dysfunction Caused by a Methyl Donor-Rich Paternal Diet

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