The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse Alzheimer’s Disease Models

Abstract

: Brains that are affected by Alzheimer’s disease (AD) are characterized by the overload of extracellular amyloid β (Aβ) peptides, but recent data from cellular and animal models propose that Aβ deposition is preceded by intraneuronal accumulation of the direct precursor of Aβ, C99. These studies indicate that C99 accumulation firstly occurs within endosomal and lysosomal compartments and that it contributes to early-stage AD-related endosomal-lysosomal-autophagic defects. Our previous work also suggests that C99 accumulation itself could be a consequence of defective lysosomal-autophagic degradation. Thus, in the present study, we analyzed the influence of the overexpression of the transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis, on C99 accumulation occurring in both AD cellular models and in the triple-transgenic mouse model (3xTgAD). In the in vivo experiments, TFEB overexpression was induced via adeno-associated viruses (AAVs), which were injected either into the cerebral ventricles of newborn mice or administrated at later stages (3 months of age) by stereotaxic injection into the subiculum. In both cells and the 3xTgAD mouse model, exogenous TFEB strongly reduced C99 load and concomitantly increased the levels of many lysosomal and autophagic proteins, including cathepsins, key proteases involved in C99 degradation. Our data indicate that TFEB activation is a relevant strategy to prevent the accumulation of this early neurotoxic catabolite.

Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?

“…TFEB activates the different steps of autophagy, from its initiation to the fusion of autophagosomes with lysosomes, but it also stimulates the biogenesis of lysosomal hydrolyses and regulates lysosomal acidification ( 191 ). Indeed, in animals, TFEB activation has been found to efficiently decrease C99 levels ( 192 , 193 , 194 ) and to ameliorate cognitive function, whereas it does not seem to produce any harmful effects in wild-type animals ( 143 ). The recent findings concerning TFEB activation by a curcumin analog are promising, because of the lack so far of specific TFEB-activating molecules.…”

The Regulation of MiTF/TFE Transcription Factors Across Model Organisms: from Brain Physiology to Implication for Neurodegeneration

“…The authors proposed a model in which TFEB plays an active role in the secretion of mutant tau via lysosomal exocytosis mediated by TFEB and Transient Receptor Potential Mucolipin 1 (TRPML1) signaling [ 125 ]. Accordingly, astrocyte-specific TFEB overexpression in the hippocampus of PS19 mice was able to reduce tau spreading from the ipsilateral to the contralateral hippocampus [ 126 ]. A recent study reported that TFEB overexpression in another AD mouse model is responsible for a reduction of the levels of the β-secretase-derived β-amyloid precursor protein fragment C99, which is a precursor of the toxic Aβ peptide.…”

The regulatory mechanism and therapeutic potential of transcription factor EB in neurodegenerative diseases

“…This suggests that TFEB activation is an important strategy for preventing the accumulation of the early neurotoxic catabolite of AD. 143 A disintegrin and metalloproteinase 10 (ADAM10)…”

“…The beneficial effects mediated by TFEB have been demonstrated in multiple mouse and cell models of AD addressing Aβ and tau pathology. 33 , 142 , 143 With respect to Aβ, TFEB overexpression rescues the autophagic flux, accelerates Aβ 1–42 degradation by regulating the autophagy‐lysosome pathway, and alleviates Aβ 1–42 ‐induced toxicity by reducing oxidative stress. 144 Similarly, intracranial stereotaxic injection of AAV‐TFEB in hippocampal neurons of APP/PS1 mice leads to a reduction of APP, Aβ production, and amyloid plaque load by accelerating flux of the endosome‐lysosome pathway.…”

“…This suggests that TFEB activation is an important strategy for preventing the accumulation of the early neurotoxic catabolite of AD. 143 A disintegrin and metalloproteinase 10 (ADAM10) has recently emerged as the major α‐secretase responsible for APP processing, 145 which plays a crucial role in axon guidance and spine density regulation. 146 , 147 There is now definitive evidence that reduction of ADAM10 activity and impaired trafficking to the synapse of ADAM10 can cause AD, thereby suggesting that inadequate ADAM10 activity is likely the cause of AD.…”