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Paolicelli RC, Jawaid A, Henstridge CM, Valeri A, Merlini M, Robinson JL, Lee EB, Rose J, Appel S, Lee VM, Trojanowski JQ, Spires-Jones T, Schulz PE, Rajendran L. TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss. Neuron. 2017 Jul 19;95(2):297-308.e6. Epub 2017 Jun 29 PubMed.
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Cambridge University
This study examines the relationships between TDP-43 inclusions, microglia, and dementia in ALS, FTLD, and AD. Work presented was from mouse or cell culture with human comparative studies. The main findings were that depletion of TDP-43 in microglia is associated with both enhanced loss of dendritic spines and synapses and enhanced Aβ clearance via microglial phagocytosis and lysosomal degradation, but not with enhanced Aβ production. Synapse and dendritic spine loss occurred independently from presence/absence of amyloid and was associated only with loss of microglial TDP-43. The human studies suggest that TDP-43 pathology is associated with lower deposition of amyloid pathology. Among ALS and FTLD-TDP patients, AD prevalence was lower compared to age-matched controls, and ALS with TDP-43 is reported to show more markers of synapse loss.
We see the following reasons to be cautious. The human comparative studies are from autopsy cohorts and are not population-representative. In the Cambridge City over 75s Cohort study (CC75C) (Keage et al., 2014), TDP-43 pathology is common and can occur in those with and those without dementia. There were significant associations between TDP-43 and neuronal loss and dementia but no significant associations between TDP-43 inclusions and amyloid deposition in this population- representative sample. Work investigating the association between TDP-43, hippocampal sclerosis, and amyloid deposition in CC75C and also the Cognitive Ageing and Function Study (CFAS) found no significant association between amyloid deposition and TDP-43 in terms of HScl neuronal loss in the older population (Hokkanen et al., 2017, submitted). TDP-43 has been previously associated with neurofibrillary tangles, but not with amyloid pathology (review Wilson et al., 2011). TDP-43 in AD may aggravate the clinical symptoms and progression of AD and in human postmortem studies, and the presence of TDP-43 is reported to be higher in AD cases. This suggests that while the interaction between TDP-43 and microglia is interesting, within the older population where most AD-type dementia occurs, the relevance of this mechanism to dementia is questionable and requires further investigation.
The associations found in the autopsy cohorts listed in Paolicelli et al. have not been controlled for sex, and the age ranges investigated suggest that this study is weighted toward the younger old. The selection of cases and controls may have biased the findings, making translation to the human population difficult. Synaptic loss through microglia activation is an interesting suggested mechanism for clinical dementia, but needs further confirmation and replication in unbiased settings. More detailed population- and community-based evaluations of TDP-43, amyloid, and synapses are needed.
As the authors cited, most studies on hypothesized toxic gain of function of TDP-43 aggregates and TDP-43 loss of function have been associated with neuronal inclusions, even though TDP-43 pathology is observed in both neurons and glia. Glial TDP-43 is frequently disregarded and the Paolicelli et al. study usefully highlights this important aspect.
It is important to note that results from studies looking at neuronal TDP-43 may be conflicting. Amyloid plaque formation has been reported to be reduced also in mice models overexpressing neuronal TDP-43 (Davis et al., 2017), as well as in mice with depletion of neuronal TDP-43 (LaClair et al., 2016). This study requires replication and investigation in other laboratory models.
AD is a complex clinicopathologically defined syndrome with many different players that cannot be reduced to simple models in the lab. It is not really possible to separate the contributions of distinct glial versus neuronal TDP-43 pathologies nor separate gain-of-function vs. loss-of function mechanisms in living systems such as mouse models, as this does not represent the actual situation in the living brain.
In summary, this work usefully highlights the role of microglia in neurodegenerative disease, but we cannot say on the basis of this evidence whether this mechanism is relevant in all neurodegenerative disease. Population studies of brain aging suggest that mechanisms related to TDP-43-associated neurodegeneration and dementia in the older population may be different from those seen in ALS and FTLD. Detailed population-based investigations of all factors associated with dementia are required to translate laboratory based findings to actual neurodegenerative disease in the human population.
Sally Hunter also contributed to this comment.
References:
Davis SA, Gan KA, Dowell JA, Cairns NJ, Gitcho MA. TDP-43 expression influences amyloidβ plaque deposition and tau aggregation. Neurobiol Dis. 2017 Jul;103:154-162. Epub 2017 Apr 20 PubMed.
Keage HA, Hunter S, Matthews FE, Ince PG, Hodges J, Hokkanen SR, Highley JR, Dening T, Brayne C. TDP-43 pathology in the population: prevalence and associations with dementia and age. J Alzheimers Dis. 2014;42(2):641-50. PubMed.
LaClair KD, Donde A, Ling JP, Jeong YH, Chhabra R, Martin LJ, Wong PC. Depletion of TDP-43 decreases fibril and plaque β-amyloid and exacerbates neurodegeneration in an Alzheimer's mouse model. Acta Neuropathol. 2016 Dec;132(6):859-873. Epub 2016 Oct 26 PubMed.
Wilson AC, Dugger BN, Dickson DW, Wang DS. TDP-43 in aging and Alzheimer's disease - a review. Int J Clin Exp Pathol. 2011;4(2):147-55. PubMed.
View all comments by Suvi HokkanenUniversitat Autònoma de Barcelona
The recent discoveries that microglia produce ASC specks, thereby contributing to Aβ plaque formation, while their capacity to remove plaques and synapses is enhanced by loss of TDP-43 highlight, once again, the paradoxical nature of the evidence regarding the role of microglia in Alzheimer's disease.
Microglia appear to do anything and the opposite. Thus, they have been reported to limit, potentiate, or have no effect on plaque formation, to aberrantly prune synapses via the complement system, to foster aberrant tau aggregation, and to be dystrophic and severely damaged by tau, which would incapacitate them to carry out any of the aforementioned protective or detrimental actions.
I doubt that a unitary explanation exists for this conflicting evidence. Rather, the problem may be that the experimental manipulations and models—e.g., pharmacological or genetic ablation of microglia, transgenic overexpression or deletion of genes identified as risk factors in GWAS, and massive overexpression of mutated APP and tau proteins—are overly aggressive and stir microglia to extreme phenotypes with little relevance to human aged brains. More experimental finesse is necessary.
I also believe that key questions remain overlooked: what the functions of microglia and their striking motility are in the adult, healthy brain, and whether these functions, whose molecular underpinnings are still poorly understood, are affected by age and genetic risk factors. The answers to these questions may help us understand the consequences of microglia malfunction in neurodegeneration.
View all comments by Elena GaleaMake a Comment
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