Neuronal-Targeted TFEB Accelerates Lysosomal Degradation of APP, Reducing Aβ Generation and Amyloid Plaque Pathogenesis

Abstract

In AD, an imbalance between A␤ production and removal drives elevated brain A␤ levels and eventual amyloid plaque deposition. APP undergoes nonamyloidogenic processing via ␣-cleavage at the plasma membrane, amyloidogenic ␤-and ␥-cleavage within endosomes to generate A␤, or lysosomal degradation in neurons. Considering multiple reports implicating impaired lysosome function as a driver of increased amyloidogenic processing of APP, we explored the efficacy of targeting transcription factor EB (TFEB), a master regulator of lysosomal pathways, to reduce A␤ levels. CMV promoter-driven TFEB, transduced via stereotactic hippocampal injections of adenoassociated virus particles in APP/PS1 mice, localized primarily to neuronal nuclei and upregulated lysosome biogenesis. This resulted in reduction of APP protein, the ␣ and ␤ C-terminal APP fragments (CTFs), and in the steady-state A␤ levels in the brain interstitial fluid. In aged mice, total A␤ levels and amyloid plaque load were selectively reduced in the TFEB-transduced hippocampi. TFEB transfection in N2a cells stably expressing APP695, stimulated lysosome biogenesis, reduced steady-state levels of APP and ␣-and ␤-CTFs, and attenuated A␤ generation by accelerating flux through the endosome-lysosome pathway. Cycloheximide chase assays revealed a shortening of APP half-life with exogenous TFEB expression, which was prevented by concomitant inhibition of lysosomal acidification. These data indicate that TFEB enhances flux through lysosomal degradative pathways to induce APP degradation and reduce A␤ generation. Activation of TFEB in neurons is an effective strategy to attenuate A␤ generation and attenuate amyloid plaque deposition in AD.

TFEB at a glance

“…Similarly, inducing TFEB activity in cellular and animal models of Hungtington's disease can reduce protein aggregation and improves neurological functions (Sardiello et al, 2009;Tsunemi et al, 2012). Furthermore, TFEB overexpression or its pharmacological activation in cellular and mouse models of Alzheimer's disease and other tauopathies can also reduce the amount of protein aggregates (Chauhan et al, 2015;Polito et al, 2014;Xiao et al, 2014Xiao et al, , 2015, which results in a reduction of neurodegeneration and improvement of behavioral deficits. Therefore, promotion of intracellular clearance through the induction of TFEB activity might represent a common therapeutic strategy for neurodegenerative disorders.…”

The Autophagy–Lysosomal Pathway in Neurodegeneration: A TFEB Perspective

“…Thus, correcting ALP defects and enhancing the activity of the pathway are appealing therapeutic interventions. Since its discovery and characterization in 2009, TFEB, a master regulator of the ALP, has been widely demonstrated to ameliorate pathology in these diseases [7–11], as well as in models of spinal and bulbar muscular atrophy and in lysosomal storage disorders (LSDs) when activated [12–15]. The broad applicability of TFEB and its role in linking the different forms of autophagy make it an exceedingly attractive therapeutic target.…”

“…The beneficial effect mediated by TFEB has been demonstrated in multiple mouse models of AD addressing Aβ and tau pathology [9–11,75]. With respect to tau, enhancing the ALP through exogenous TFEB expression in the brain dramatically reduces tau pathology, neurodegeneration, and behavioral deficits in the rTg4510 mouse model [10].…”

Protease-resistant modified human β-hexosaminidase B ameliorates symptoms in GM2 gangliosidosis model

“…(AD) model (APP/PS1) mice, could be induced by using AAV gene transfer of transcription factor EB (TFEB), a master regulator of lysosomal degradative pathways, involving upregulation of lysosomal biogenesis and autophagy (46). These findings suggest that not only primary defects of enzymes and functional proteins, but also the secondary dysregulation in metabolic homeostasis, are the main causes of neurodegenerative diseases, including LSDs, PD, and AD due to intracellular accumulation of glycoconjugates, lipids, and proteins, leading to the abnormal functions of organelle and degradative machineries.…”