TDP-43 pathological changes in early onset familial and sporadic Alzheimer’s disease, late onset Alzheimer’s disease and Down’s Syndrome: association with age, hippocampal sclerosis and clinical phenotype

Davidson, Yvonne; Raby, Samantha; Foulds, Penelope; Robinson, Andrew C; Thompson, James C.; Sikkink, Stephen; Yusuf, Imran H.; Amin, Hanan; DuPlessis, Daniel; Troakes, Claire; Al‐Sarraj, Safa; Sloan, Carolyn; Esiri, Margaret M.; Prasher, V. P.; Allsop, David; Neary, David; Pickering‐Brown, Stuart; Snowden, Julie S.; Mann, David

doi:10.1007/s00401-011-0879-y

Cited by 138 publications

(132 citation statements)

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“…TDP-43 has been discovered in both sporadic and familial AD [46][47][48] , and our seeding results showed that TDP-43 oligomers can interact and influence Ab fibrillization. The increased Ab assembly in the presence of TDP-43 could result from a seeding effect that generates new Ab assemblies such as Ab*56 and larger aggregates or formation of cross-linked TDP-43 and Ab complexes.…”

Section: Discussionmentioning

confidence: 54%

Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

et al. 2014

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Proteinaceous inclusions are common hallmarks of many neurodegenerative diseases. TDP-43 proteinopathies, consisting of several neurodegenerative diseases, including frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS), are characterized by inclusion bodies formed by polyubiquitinated and hyperphosphorylated full-length and truncated TDP-43. The structural properties of TDP-43 aggregates and their relationship to pathogenesis are still ambiguous. Here we demonstrate that the recombinant full-length human TDP-43 forms structurally stable, spherical oligomers that share common epitopes with an anti-amyloid oligomer-specific antibody. The TDP-43 oligomers are stable, have exposed hydrophobic surfaces, exhibit reduced DNA binding capability and are neurotoxic in vitro and in vivo. Moreover, TDP-43 oligomers are capable of cross-seeding Alzheimer's amyloid-b to form amyloid oligomers, demonstrating interconvertibility between the amyloid species. Such oligomers are present in the forebrain of transgenic TDP-43 mice and FTLD-TDP patients. Our results suggest that aside from filamentous aggregates, TDP-43 oligomers may play a role in TDP-43 pathogenesis.

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Section: Discussionmentioning

confidence: 54%

Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

et al. 2014

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“…Although some studies on HS‐Aging explicitly state a sparing of CA2/3 in HS‐Aging diagnosis 16, 17, 24, 27, 31, 55, others include cases which present with neuron loss also in other hippocampal sectors than the CA1 and subiculum 15, 29, 43, 44, 57, 58. Frequently, the term “selective” is used for CA1 neuron loss and gliosis, but how potential lesions in other CA areas are considered is not further specified (for example 2, 7, 26, 35).…”

Section: Discussionmentioning

confidence: 99%

Hippocampal sclerosis, hippocampal neuron loss patterns and TDP‐43 in the aged population

et al. 2017

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Hippocampal neuron loss is a common neuropathological feature in old age with various underlying etiologies. Hippocampal sclerosis of aging (HS‐Aging) is neuropathologically characterized by severe CA1 neuronal loss and frequent presence of transactive response DNA‐binding protein of 43 kDa (TDP‐43) aggregations. Its etiology is unclear and currently no standardized approaches to measure HS‐Aging exist. We developed a semi‐quantitative protocol, which captures various hippocampal neuron loss patterns, and compared their occurrence in the context of HS‐Aging, TDP‐43, vascular and tau pathology in 672 brains (TDP‐43 staining n = 642/672, 96%) donated for the population‐based Cambridge City over‐75s Cohort and the Cognitive Function and Ageing Study. HS‐Aging was first evaluated independently from the protocol using the most common criteria defined in literature, and then described in detail through examination of neuron loss patterns and associated pathologies. 34 (5%) cases were identified, with a maximum of five pyramidal neurons in each of over half CA1 fields‐of‐view (x200 magnification), no vascular damage, no neuron loss in CA2‐CA4, but consistent TDP‐43 neuronal solid inclusions and neurites. We also report focal CA1 neuron loss with vascular pathology to affect predominantly CA1 bordering CA2 (Fisher's exact, P = 0.009), whereas neuron loss in the subicular end of CA1 was associated with TDP‐43 inclusions (Fisher's exact, P < 0.001) and high Braak stage (Fisher's exact, P = 0.001). Hippocampal neuron loss in CA4‐CA2 was not associated with TDP‐43. We conclude that hippocampal neuron loss patterns are associated with different etiologies within CA1, and propose that these patterns can be used to form objective criteria for HS‐Aging diagnosis. Finally, based on our results we hypothesize that neuron loss leading to HS‐Aging starts from the subicular end of CA1 when it is associated with TDP‐43 pathology, and that this neurodegenerative process is likely to be significantly more common than “end‐stage” HS‐Aging only.

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“…Indeed, observations of AD-DS neuropathology already underpin our mechanistic Pathological features other than plaques and NFTs also develop in both AD-DS and LOAD. Neuronal accumulation of ubiquitylated and aggregated transactive response DNA-binding protein 43 (TDP43; also known as TARDBP) in the cytoplasm and neurites is similar in AD-DS (7-14% of cases) and familial AD (10-14% of cases), whereas TDP43 neuropathology occurs more frequently in LOAD (29-79% of cases), perhaps because of the later disease onset 101,102 . Lewy bodies, particularly in the amygdala, occur at a similar frequency in AD-DS and LOAD 103 , but dementia with Lewy bodies (DLB), which is characterized by cognitive decline with hallucinations and parkinsonism features, is rare in DS 104 .…”

Section: Neuropathological Changes In Ad-dsmentioning

confidence: 99%

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

et al. 2015

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Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP) -an Alzheimer disease risk factor -although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.Down syndrome (DS) is a complex, highly variable disorder that arises from trisomy of chromosome 21. It was one of the first chromosomal disorders to be identified 1 and occurs with an incidence of approximately 1 in 800 births 2 . Its prevalence within a given population is influenced by infant mortality rates, access to health care, termination rates, average maternal age 3 and life expectancy. Indeed, despite the increased availability of prenatal diagnosis and access to the option of termination, the global prevalence of DS is rising because of improvements in life expectancy: the number of adults with DS aged over 40 years has doubled in northern Europe since 1990 and, in the United Kingdom, one-third of the estimated 40,000 people with DS are thought to be over 40 years of age 4 .DS is the most common form of intellectual disability. In addition to the features that are found in everyone with the disorder, such as the characteristic facial dysmorphology, there are many DS-associated phenotypes that have variable penetrance and severity. For example, approximately 40% of individuals with DS have heart malformations (usually atrioventricular septal defects) 5 . A key feature of DS is a striking propensity to develop early-onset Alzheimer disease (EOAD). Complete trisomy of chromosome 21 universally causes the development of amyloid plaques and neurofibrillary tangles (NFTs), which are typical characteristics of AD brain pathology, by the age of 40, and approximately twothirds of individuals with DS develop dementia by the age of 60 (REFS 6,7). However, rates of dementia do not reach 100%, even in older individuals, suggesting that some individuals with DS are protected from the onset of AD (FIG. 1).All of the features of DS arise because of aberrant dosages of coding and/or non-coding sequences present on chromosome 21. Among these sequences, the gene encoding amyloid precursor protein (APP) is thought to have a key role in the pathology of AD. The additional copy of APP may drive the development of AD in individuals with DS (AD-DS) by increasing the levels of amyloid-β (Aβ), a cleavage product of APP that misfolds and accumulates in the brain in people with AD. Consistent with this hypothesis, individuals with small internal chromosome 21 duplications that result in three copies of APP -a rare familial trait known as duplic...

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TDP-43 pathological changes in early onset familial and sporadic Alzheimer’s disease, late onset Alzheimer’s disease and Down’s Syndrome: association with age, hippocampal sclerosis and clinical phenotype

Cited by 138 publications

References 38 publications

Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients

Hippocampal sclerosis, hippocampal neuron loss patterns and TDP‐43 in the aged population

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

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