Tau and TDP-43 synergy: a novel therapeutic target for sporadic late-onset Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is traditionally defined by the presence of two types of protein aggregates in the brain: amyloid plaques comprised of the protein amyloid-β (Aβ) and neurofibrillary tangles containing the protein tau. However, a large proportion (up to 57%) of AD patients also have TDP-43 aggregates present as an additional comorbid pathology. The presence of TDP-43 aggregates in AD correlates with hippocampal sclerosis, worse brain atrophy, more severe cognitive impairment, and more rapid cognitive decline. In patients with mixed Aβ, tau, and TDP-43 pathology, TDP-43 may interact with neurodegenerative processes in AD, worsening outcomes. While considerable progress has been made to characterize TDP-43 pathology in AD and late-onset dementia, there remains a critical need for mechanistic studies to understand underlying disease biology and develop therapeutic interventions. This perspectives article reviews the current understanding of these processes from autopsy cohort studies and model organism-based research, and proposes targeting neurotoxic synergies between tau and TDP-43 as a new therapeutic strategy for AD with comorbid TDP-43 pathology.

LATE-NC aggravates GVD-mediated necroptosis in Alzheimer’s disease

“…Taken together, our findings provide evidence for the synergy between pathologically aggregated proteins contributing to neuronal loss in AD, as already suggested by others [ 11 , 27 , 43 , 61 , 67 ]. Here, the absence of LATE-NC in patients with AD was associated with attenuated neuronal loss, even in the presence of intracellular pTau lesions and Aβ plaques.…”

“…The reason for this discrepancy in age at death is the result of the age-related frequencies of Aβ and pTau pathologies that explains why most cases without ADNC are 65 years of age or younger while symptomatic AD cases with end-stage ADNC are usually 70 years or older [9]. Taken together, our findings provide evidence for the synergy between pathologically aggregated proteins contributing to neuronal loss in AD, as already suggested by others [11,27,43,61,67]. Here, the absence of LATE-NC in patients with AD was associated with attenuated neuronal loss, even in the presence of intracellular pTau lesions and Aβ plaques.…”

“…5 ). Therefore, our results argue in favor of developing personalized treatment strategies that consider co-morbid pathologies [ 43 , 76 ], with GVD-mediated necroptosis being a presumably very important downstream target in this context.…”

“…Previously, we observed a strong correlation between pMLKL-positive GVD and Braak NFT stages [ 41 ]. Furthermore, we found that TDP-43 co-localizes and interacts with pTau lesions during AD progression [ 75 ], suggesting a synergy between these proteins [ 43 ]. In ALS/FTLD, we showed that TDP-43 and tau pathologies contributed to pMLKL-positive GVD in neurons of the CA1 subfield of the hippocampus [ 79 ].…”

Tau-Neurodegenerationmismatchreveals vulnerability and resilience to comorbidities in Alzheimer’s continuum

“…argyrophilic grain disease), a particularly important pathology associated with limbic involvement is TDP-43, especially in the form of LATE, which is a common co-pathology with AD. LATE has previously been shown to accelerate cognitive progression and hippocampal atrophy when co-occurring with AD relative to AD alone 6,37 although can also occur independently 33 . The pattern observed in the limbic vulnerable group is consistent with expected regional distribution of pathology and atrophy observed in TDP-43 proteinopathy 20,33,38 .…”