TDP-43 proteinopathy in aging: Associations with risk-associated gene variants and with brain parenchymal thyroid hormone levels
Introduction
Hippocampal sclerosis of aging (HS-Aging) is a neurodegenerative disease, distinct from Alzheimer's disease (AD) (Montine et al., 2012; Nelson et al., 2013), yet often mimicking AD clinically (Brenowitz et al., 2014; Murray et al., 2014; Nelson et al., 2013; Pao et al., 2011; Zarow et al., 2012). HS-Aging is a very prevalent condition, affecting 10–25% of persons over age 85 (Brenowitz et al., 2014; Kero et al., 2018; Leverenz et al., 2002; Nelson et al., 2011; Zarow et al., 2012). The defining characteristics of HS-Aging are neuronal loss, astrocytosis, and transactive response DNA binding protein of 43 kDa (TDP-43) pathology in the hippocampus (Amador-Ortiz and Dickson, 2008; Nelson et al., 2011), and these pathologic features are specifically associated with cognitive impairment (Brenowitz et al., 2014; Murray et al., 2014; Nag et al., 2017; Nelson et al., 2010). “TDP-43 pathology” refers to phosphorylated TDP-43 detected via immunohistochemistry, and localized in cytoplasmic, nuclear, perivascular, and/or neurite-like structures. Currently, the upstream disease-driving mechanisms associated with TDP-43 pathology and HS-Aging are not well understood. Thyroid hormone (TH) signaling, and/or comorbid AD-type plaques and tangles, may affect persons' vulnerability to HS-Aging pathology, and disease susceptibility factors may also overlap with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) (Dickson et al., 1994; Josephs et al., 2008; Katsumata et al., 2018; Nelson et al., 2013, Nelson et al., 2016a; Zarow et al., 2008, Zarow et al., 2012).
The identification of genetic risk factors for HS-Aging has provided insights into disease mechanisms. Specific variants in genes (GRN and TMEM106B) that previously were associated with risk for FTLD-TDP, were later also linked with risk for HS-Aging pathology and age-related TDP-43 pathology, which probably represent a disease continuum previously referred to together as cerebral age-related TDP-43 pathology with sclerosis (Cykowski et al., 2017; Dickson et al., 2010, Dickson et al., 2015; Murray et al., 2014; Nelson et al., 2016b; Rutherford et al., 2012; Van Langenhove et al., 2012). These prior studies support the hypothesis that GRN and TMEM106B gene variants influence the brain's vulnerability to developing TDP-43 pathology. There also is compelling evidence that TDP-43 pathology is comorbid with advanced AD-type plaques and tangles in the medial temporal lobe structures in many persons (Davidson et al., 2011; Josephs et al., 2008, Josephs et al., 2016; Nelson et al., 2018). However, the associations between GRN/TMEM106B gene variants, AD-type pathology, and TDP-43 pathology are inconsistent, so other factors must also be relevant.
The only genome-wide association study published to date that focused exclusively on autopsy-confirmed HS-Aging pathology as the endophenotype identified a single nucleotide polymorphism (SNP) in ABCC9 that was associated with risk for HS-Aging pathology (Nelson et al., 2014). In a non-overlapping group of autopsied subjects, the association between the same ABCC9 SNP and HS-Aging pathology was replicated (Nelson et al., 2015b). These same gene variants in ABCC9 were associated with brain atrophy (Nho et al., 2016), and nearby polymorphisms were also linked to dementia risk in APOE ε4(-) individuals (D'Introno et al., 2006; Mayeux et al., 2002; Pericak-Vance et al., 1997; Scott et al., 1999).
Approximately one million base-pairs away on Chr. 12p12 from ABCC9 is SLCO1C1 (Jansen et al., 2005), which encodes the brain's main thyroid hormone (TH) importing protein. Importantly, Roostaei et al. discovered a novel Chr. 12p12 SNP based on its association with non-Aβ neurodegeneration (Roostaei et al., 2016), and this SNP status also was shown to be associated with variability in SLCO1C1 expression in human brain (Nelson et al., 2016a). Both ABCC9 and SLCO1C1 transcripts are highly expressed in human astrocytes (Nelson et al., 2016a), and their functions appear interconnected. Astrocytes import TH from blood into brain, process blood-borne thyroxine (T4) hormone into the biologically active triiodothyronine (T3), and deliver T3 to neurons (Heuer and Visser, 2009; Morte and Bernal, 2014). The ABCC9 polypeptide (also known as SUR2) serves as a metabolic sensor that helps couple energy needs with blood flow and intracellular signaling (Nelson et al., 2015a; Nichols, 2006; Nichols et al., 2013), whereas the TH importing SLCO1C1 polypeptide is also known as OATP1C1 and Thyroxine transporter (Bernal et al., 2015; Jansen et al., 2005). TH is a potent metabolic regulating agent (McAninch and Bianco, 2014; Mullur et al., 2014; Trentin, 2006; van der Deure et al., 2008), whereas TH dysregulation has been previously associated with dementia risk (Chaker et al., 2016; Mafrica and Fodale, 2008; Sampaolo et al., 2005; Tan and Vasan, 2009) and HS-Aging specifically (Nelson et al., 2016a; Trieu, 2018). Together, these observations provide the basis for a plausible mechanistic hypothesis: gene variants that affect TH levels in the brain appear to be relevant to TDP-43/HS-Aging pathology. Much remains unknown about the biochemical landscape of the aged brain, and the impact of genetics. For example, a separate GWAS found that a SNP (rs9637454) in a gene encoding a distinct K+ channel modifying protein – KCNMB2 – was also linked to HS-Aging risk (Beecham et al., 2014).
The main objectives of the present study were to analyze the pathologic, genetic, and biochemical parameters that can be correlated with TDP-43/HS-Aging pathology in the aged human hippocampus. We tested whether gene variants associated with altered HS-Aging risk also are associated with variation in brain TH processing. The data were gathered from research volunteers followed to autopsy in the University of Kentucky Alzheimer's Disease Center (UK-ADC) cohort. Results of these analyses provide support of the hypothesis that TH related pathways in the brain may alter vulnerability to TDP-43 pathology and HS-Aging.
Section snippets
UK-ADC autopsy cohort
Details of UK-ADC research volunteers' recruitment, the overall cohort inclusion/exclusion criteria, and clinical assessments were described previously (Jicha et al., 2012; Schmitt et al., 2012). Briefly, older adult volunteers (most recruited while cognitively normal) agreed to be followed annually for cognitive, physical, and neurological examination and to donate their brain at the time of death, with a provision to allow genetic testing for research purposes. Protocols and informed consent
Results
An underlying a priori hypothesis for the current study is shown in Fig. 1, and the workflow is depicted in Supplemental Fig. 1. The overall goals were to analyze genetic, clinical, pathologic, and biochemical (related to TH) variables, in order to test hypotheses related to pathogenesis of TDP-43 pathology and HS-Aging. The data analyzed derived from a convenience sample based on availability of brain tissue for biochemistry, with the goal of including a relatively broad range of ages,
Discussion
To explore evidence of disease-associated mechanisms relevant to TDP-43 proteinopathy in aged human brains, a multimodal (clinical, pathologic, genetic, and biochemical) data set was generated and analyzed from volunteers participating in a well-characterized autopsy cohort. As in another high-quality community-based cohort (Nag et al., 2018), slightly under 50% of the cases in the present study were positive for TDP-43 inclusions. A focal point of the present study was T3 and T4 levels in
Competing interests
The authors report no competing interests.
Funding support
Funding included grants P30 AG028383, R01 AG057187, and R01 AG042475 from the National Institute on Aging (NIA)/National Institutes of Health (NIH).
Acknowledgements
We are deeply grateful to all of the study participants, clinical workers, and researchers that made this study possible. Special thanks to Sonya Anderson and Ela Patel for work in biobanking and neurohistology.
References (98)
- et al.
Neuropathology of hippocampal sclerosis
Handb. Clin. Neurol.
(2008) Reduced tissue thyroid hormone levels in fatal illness
Metabolism
(1993)Thyroid hormones and brain development
Vitam. Horm.
(2005)Treated hypothyroidism is associated with cerebrovascular disease but not Alzheimer's disease pathology in older adults
Neurobiol. Aging
(2018)Age-dependent association of thyroid function with brain morphology and microstructural organization: evidence from brain imaging
Neurobiol. Aging
(2018)Thyroid hormone and astrocyte differentiation
Vitam. Horm.
(2018)Current knowledge of chromosome 12 susceptibility genes for late-onset Alzheimer's disease
Neurobiol. Aging
(2006)Post-ischaemic thyroid hormone treatment in a rat model of acute stroke
Brain Res.
(2013)Evolution of ligands, receptors and metabolizing enzymes of thyroid signaling
Mol. Cell. Endocrinol.
(2017)Preclinical AD workgroup staging: pathological correlates and potential challenges
Neurobiol. Aging
(2012)