TDP‐43 pathology in Alzheimer's disease, dementia with Lewy bodies and ageing

Abstract

Intracellular inclusions consisting of TAR DNA binding protein-43 (TDP-43 pathology) are present in up to 57% of Alzheimer's disease (AD) cases and follow a distinct topographical pattern of progression described in the TDP-43 in AD staging scheme. This scheme has not been applied to the assessment of TDP-43 pathology in dementia with Lewy bodies (DLB) and aged controls. We investigated TDP-43 pathology prevalence and severity in AD, DLB, mixed AD/DLB (Mx AD/DLB) and aged controls. One hundred and nineteen human post-mortem brains were included, neuropathologically diagnosed as AD: 46, DLB: 15, Mx AD/DLB: 19 and aged controls: 39. Paraffin sections inclusive of the amygdala, hippocampus, striatum and neocortex were immunohistochemically stained with antibodies against phosphorylated TDP-43 and staged according to the TDP-43 in AD staging scheme. TDP-43 pathology was present in all groups: AD: 73.9%, DLB: 33.3%, Mx AD/DLB: 52.6% and controls: 17.9%. Prevalence of TDP-43 pathology was significantly higher in AD and Mx AD/DLB compared to controls. In controls, higher age at death was associated with prevalence of TDP-43 pathology and higher TDP-43 in AD stage, suggesting that this type of TDP-43 pathology may partly be an age-associated phenomenon. Significantly higher prevalence of TDP-43 pathology in the AD group indicates that AD pathology possibly triggers and aggravates TDP-43 pathology. The validity of the TDP-43 in AD staging scheme is not limited to AD and should be applied to assess TDP-43 pathology in post mortem brains of aged individuals to further elucidate the role of TDP-43 pathology in age associated neurodegeneration.

Interactions of pathological proteins in neurodegenerative diseases

“…Recently, Josephs and colleagues reported that TDP-43 pathology in AD is seen in over 50% of cases where it spreads in a distinct pattern [70, 71], which was also observed in LBD and aged controls by others [95]. Moreover, colocalization of phosphorylated TDP-43 and τ-containing NFTs has been reported but it is not yet clear whether this finding is due to unspecific co-staining of NFTs with the pTDP-43 antibody or whether indeed phosphorylated TDP-43 accumulates in NFTs.…”

“…Respective data from neuropathological post-mortem studies are corroborated by in vivo imaging studies showing higher amyloid and τ levels in LBD compared to controls [46, 47]. While AD pathology is the most important co-morbidity in LBD cases, they may also show other pathologies such as cerebrovascular disease to varying degrees of severity in up to 75% [67] and TDP-43 pathology in over 30% of cases [95]. More quantitative data on the amount of pathological burden in large clinico-pathological cohorts are needed to clarify the relative influence of Aβ, τ, α-syn, and TDP-43 on the clinical picture.…”

“…1Pathological proteins accumulate with increasing age as measured in large post-mortem studies. Age-related prevalence of NFTs ( a , n  = 1310), Aβ plaques ( b , n  = 849), neuritic plaques ( c , n  = 662), AD pathology as defined by NIA-AA ( d , n  = 662), TDP-43 pathology ( e , n  = 147), and Lewy body pathology ( f , n  = 582) (reevaluation of previously published cases by the authors (JA, DRT) [95, 139, 146, 147]). The prevalence for NFTs is provided separately for each Braak-NFT stage (I–VI) [12] ( a ) and that for Aβ plaques separately for each phase of Aβ-plaque deposition as determined in medial temporal lobe sections ( 1 – 4 ) [144] corresponding with the plaques extension all over the entire brain [143].…”

“…In PD, pathology begins in brainstem and spreads up through midbrain to cortex. In DLB, pathology begins in cortex and spreads “down”MSA-P (striato-nigral degeneration with parkinsonism (SDN)): lesions mainly in the striatum and the substantia nigra; gray and white matter pathologyMSA-C (olivo-ponto-cerebellar atrophy, OPCA): lesions mainly in the pons, medulla oblongata, and the cerebellum; gray and white matter pathologyAβ pathology (over 80% of cases) [61]NFT and NT at Braak stage >II (over 50% of cases) [61]TDP-43 pathology (over 30%) [95]Amyotrophic lateral sclerosis (ALS)TDP-43, FUS, ubiquilin, C9orf72 translated intronic repeat, SOD1Cytoplasmic, nuclear (neurons and oligodendrocytes)Motor cortex, spinal cord, other cortical regionsNeurofibrillary tangles (78%), atherosclerosis (35%); β-amyloid (35%); tauopathy/tau inclusions (17%), Lewy body formation (11%), microinfarcts (7%), and α-syn (4%) [24]τ- and α-syn pathology in cases of the Kii-Peninsula variant in the temporal lobe, striatum brain stem, cerebellum [82, 102]FTLD-TDP, FTLD-FUSTDP-43, FUS, ubiquilin, C9orf72 translated intronic repeatCytoplasmic, nuclear inclusions in neurons and glial cellsFrontotemporal neocortex and medial temporal lobe …”

Circadian Rhythms in AD Pathogenesis: a Critical Appraisal

“…We know that mixed neurodegenerative pathology is present in many if not most dementia patients, as evidence of α-synuclein, TDP-43, and vascular disesae are often observed alongside the typical Aβ plaques and tau neurofibrillary tangles[66–68]. The potential contributions of these other pathologies to circadian dysfunction are unknown.…”