Fig. 3

Illustration of the involvement of TDP-43 in the progression of Alzheimer’s disease. In the brain of Alzheimer’s disease (AD), the amyloid-β (Aβ) peptide is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP) by β- and γ-secretases. The accumulation of soluble Aβ monomers in the brain parenchyma leads to the formation of Aβ oligomers, fibrils, and eventually Aβ plaques, due to overproduction and/or impaired Aβ clearance pathways contributing to the development of AD. The pathological changes of tau protein decrease its microtubule binding capacity and disrupts microtubule stability causing microtubule disintegration. The intracellular aggregates of tau protein form the neurofibrillary tangles. Tau deposits are also found in neuronal cell processes (“neuropil threads”) and in dystrophic neurites within Aβ plaques. Aβ plaques are heterogeneous lesions containing not only amyloid deposits and tau-positive neurites, but also neurites with degenerating pre- and post-synaptic elements (neurite dystrophy), as well as activated microglia, reactive astrocytes, and dysfunction of oligodendrocytes causing demyelination. TDP-43 is synthesized in the cytoplasm and retains the ability to shuttle from the cytoplasm into the nucleus where it primarily resides to perform its physiological functions such as RNA splicing. During the progression of AD, the pathogenic events lead to TDP-43 depletion from the nucleus, TDP-43 mislocalization into the cytoplasm, and the formation of insoluble TDP-43 aggregates. The neurodegeneration brought about by pathological TDP-43 can be caused by a potential combination of both a loss of physiological function and a gain of toxic functions