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.

Keywords: Alzheimer’s disease; Amyloid-β (Aβ); Frontotemporal lobar degeneration (FTLD); Limbic-predominant age-related TDP-43 encephalopathy (LATE); TDP-43; Tau.

Fig. 1

Pathways of neurodegeneration and cognitive impairment in AD. The human brain is subject to a variety of factors, both genetic and environmental, that either incite (orange) or mitigate (blue) the risk of developing the neuropathologic hallmarks of Alzheimer’s disease (amyloid plaques and neurofibrillary tangles). It is currently unknown whether these factors also influence the development of TDP-43 proteinopathy. While initiation of amyloid, tau, or TDP-43 pathology may occur through independent or overlapping events, the presence of multiple pathologies likely drives synergistic neurotoxicity that leads to cognitive decline and neurodegeneration. Observational data from human autopsy studies, as well as work from model systems, suggest that TDP-43 pathology enhances tau deposition and exacerbates the clinical severity of AD

Fig. 2

Potential mechanisms for tau and TDP-43 synergy in AD. There are numerous pathways that potentially underlie tau and TDP-43 synergistic neurotoxicity. These include interactions within the nucleus during regulated transport between the nucleus and cytoplasm, or associations with DNA, RNA, or nuclear speckles. In the cytoplasm, alterations in microtubule dynamics, stability, or transport along microtubules, derangement of cellular signaling including post-translational modifications such as phosphorylation, ubiqitination, acetylation, or SUMOylation, or formation of stress granules could lead to phenotypic enhancement of tau and TDP-43. Finally, misfolded tau or TDP-43 protein can impair normal cellular proteostasis mechanisms, which may have a broader impact on other aggregation prone proteins