TDP-43 inclusions are found in many Alzheimer’s disease (AD) patients presenting faster disease progression and greater brain atrophy. Previously, we showed full-length TDP-43 forms spherical oligomers and perturbs amyloid-β (Aβ) fibrillization. To elucidate the role of TDP-43 in AD, here, we examined the effect of TDP-43 in Aβ aggregation and the attributed toxicity in mouse models. We found TDP-43 inhibited Aβ fibrillization at initial and oligomeric stages. Aβ fibrillization was delayed specifically in the presence of N-terminal domain containing TDP-43 variants, while C-terminal TDP-43 was not essential for Aβ interaction. TDP-43 significantly enhanced Aβ’s ability to impair long-term potentiation and, upon intrahippocampal injection, caused spatial memory deficit. Following injection to AD transgenic mice, TDP-43 induced inflammation, interacted with Aβ, and exacerbated AD-like pathology. TDP-43 oligomers mostly colocalized with intracellular Aβ in the brain of AD patients. We conclude that TDP-43 inhibits Aβ fibrillization through its interaction with Aβ and exacerbates AD pathology.
Alzheimer's disease (AD) is a neurodegenerative disease characterized by an excessive inflammatory response and impaired memory retrieval, including spatial memory, recognition memory, and emotional memory. Acquisition and retrieval of fear memory help one avoid dangers and natural threats. Thus, it is crucial for survival. AD patients with impaired retrieval of fear memory are vulnerable to dangerous conditions. Excessive expression of inflammatory markers is known to impede synaptic transmission and reduce the efficiency of memory retrieval. In wild-type mice, reducing inflammation response can improve fear memory retrieval; however, this effect of this approach is not yet investigated in 3xTg-AD model mice. To date, no satisfactory drug or treatment can attenuate the symptoms of AD despite numerous efforts. In the past few years, the direction of therapeutic drug development for AD has been shifted to natural compounds with anti-inflammatory effect. In the present study, we demonstrate that the compound 4-(phenylsulfanyl) butan-2-one (4-PSB-2) is effective in enhancing fear memory retrieval of wild-type and 3xTg-AD mice by reducing the expression of TNF-α, COX-2, and iNOS. We also found that 4-PSB-2 helps increase dendritic spine density, postsynaptic density protein-95 (PSD-95) expression, and long-term potentiation (LTP) in the hippocampus of 3xTg-AD mice. Our study indicates that 4-PSB-2 may be developed as a promising therapeutic compound for treating fear memory impairment of AD patients.
TDP-43 proteinopathies cover a range of neurodegenerative
diseases,
including frontotemporal lobar degeneration (FTLD) and amyotrophic
lateral sclerosis (ALS). Hyperphosphorylated TDP-43 was found within
the inclusion bodies in disease lesions; however, the role of hyperphosphorylation
and the toxic species are still ambiguous. To characterize the hyperphosphorylation
effect of TDP-43, here, we employed five serine mutations implicated
in the diseases at serine locations 379, 403, 404, 409, and 410 in
the C-terminus to aspartate (S5D) and to alanine (S5A). We systematically
characterized the conformation, liquid–liquid phase separation,
oligomerization, and fibrillization of TDP-43 variants. Results revealed
that the recombinant TDP-43 variants readily formed structurally similar
spherical oligomers, as evidenced by circular dichroism spectroscopy,
fluorescence spectroscopy, the TDP-43 oligomer-specific antibody assay,
dynamic light scattering, and transmission electron microscopy. After
incubation, only the phosphor-mimic S5D TDP-43 formed thioflavin-positive
amyloid fibrils, whereas wild-type and S5A TDP-43 formed amorphous
aggregates. We also examined membrane disruption, the cytotoxicity
of human neuroblastoma, and the synaptic loss of primary neurons induced
by oligomers and large aggregates of TDP-43. The results showed that
all oligomeric TDP-43 variants were toxic regardless of hyperphosphorylation,
but the fibrils and amorphous aggregates were not. Overall, our results
demonstrated the hyperphosphorylation effect on fibril formation and
the toxicity attributed from TDP-43 oligomers. This study facilitates
the understanding and therapeutic development for TDP-43 proteinopathies.
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