A partial reduction of VDAC1 enhances mitophagy, autophagy, synaptic activities in a transgenic Tau mouse model

Abstract

Alzheimer's disease (AD) is the most common cause of mental dementia in the aged population. AD is characterized by the progressive decline of memory and multiple cognitive functions, and changes in behavior and personality. Recent research has revealed age‐dependent increased levels of VDAC1 in postmortem AD brains and cerebral cortices of APP, APPxPS1, and 3xAD.Tg mice. Further, we found abnormal interaction between VDAC1 and P‐Tau in the AD brains, leading to mitochondrial structural and functional defects. Our current study aimed to understand the impact of a partial reduction of voltage‐dependent anion channel 1 (VDAC1) protein on mitophagy/autophagy, mitochondrial and synaptic activities, and behavior changes in transgenic TAU mice in Alzheimer's disease. To determine if a partial reduction of VDAC1 reduces mitochondrial and synaptic toxicities in transgenic Tau (P301L) mice, we crossed heterozygote VDAC1 knockout (VDAC1+/−) mice with TAU mice and generated double mutant (VDAC1+/−/TAU) mice. We assessed phenotypic behavior, protein levels of mitophagy, autophagy, synaptic, other key proteins, mitochondrial morphology, and dendritic spines in TAU mice relative to double mutant mice. Partial reduction of VDAC1 rescued the TAU‐induced behavioral impairments such as motor coordination and exploratory behavioral changes, and learning and spatial memory impairments in VDAC1+/−/TAU mice. Protein levels of mitophagy, autophagy, and synaptic proteins were significantly increased in double mutant mice compared with TAU mice. In addition, dendritic spines were significantly increased; the mitochondrial number was significantly reduced, and mitochondrial length was increased in double mutant mice. Based on these observations, we conclude that reduced VDAC1 is beneficial in symptomatic‐transgenic TAU mice.

Reduced VDAC1, Maintained Mitochondrial Dynamics and Enhanced Mitochondrial Biogenesis in a Transgenic Tau Mouse Model of Alzheimer’s Disease

“…In summary, the findings of the current study, together with our earlier studies of synaptic, mitophagy, autophagy, transmission electron microscopy, and behavioral phenotype analysis [ 19 ] provided evidence of the protective effects of reduced VDAC1 against the mitochondrial and synaptic toxicities induced by P-TAU in TAU (P301L) mice. These findings also offered new evidence to support the development of VDAC1 therapeutic strategies for AD.…”

“…In mutant TAU mice, we examined the protective effects of a partial decrease in VDAC1 against the TAU-induced mitochondrial dysfunction. Through the process of breeding mutant TAU mice with VDAC1 heterozygote knockout (VDAC1 +/− ) mice, we were able to generate double-mutant animals [ 19 ]. In the preliminary investigation, using immunoblotting and immunofluorescence analysis, we measured the protein levels of mitochondrial dynamics and mitochondrial biogenesis in 6-month-old WT, VDAC1 +/− , TAU, and VDAC1 +/− /TAU mice.…”

“…Data are from three independent experiments showed similar results (N = 3). Three animals were randomly selected from each group/genotype for immunoblotting and immunofluorescence analyses from a total of ten animals studied for behavioral phenotype [ 19 ]. ( C ) Representative immunofluorescence images of 10-micron coronal sections (10×).…”

“…Further, in a recent study of VDAC1 +/− /TAU mice, we showed that a partial decrease in VDAC1 reversed the TAU-induced behavioral deficits in VDAC1 +/− /TAU mice compared to TAU animals. These behavioral impairments included motor coordination and exploratory behavioral alterations, as well as learning and spatial memory impairments [ 19 ]. In comparison to TAU animals, the protein levels of synaptic proteins, mitophagy proteins, and autophagy proteins were dramatically elevated in double-mutant mice.…”

“…In comparison to TAU animals, the protein levels of synaptic proteins, mitophagy proteins, and autophagy proteins were dramatically elevated in double-mutant mice. In addition to this, the number of dendritic spines was greatly increased, the number of mitochondria was significantly decreased, and the length of the mitochondria was significantly raised in double-mutant mice [ 19 ]. However, it is unclear whether a partial reduction in VDAC1 expression reduces mitochondrial fission, and increases fusion and biogenesis activities.…”