Insights from Drosophila on Aβ- and tau-induced mitochondrial dysfunction: mechanisms and tools

Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative dementia in older adults worldwide. Sadly, there are no disease-modifying therapies available for treatment due to the multifactorial complexity of the disease. AD is pathologically characterized by extracellular deposition of amyloid beta (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. Increasing evidence suggest that Aβ also accumulates intracellularly, which may contribute to the pathological mitochondrial dysfunction observed in AD. According with the mitochondrial cascade hypothesis, mitochondrial dysfunction precedes clinical decline and thus targeting mitochondria may result in new therapeutic strategies. Unfortunately, the precise mechanisms connecting mitochondrial dysfunction with AD are largely unknown. In this review, we will discuss how the fruit fly Drosophila melanogaster is contributing to answer mechanistic questions in the field, from mitochondrial oxidative stress and calcium dysregulation to mitophagy and mitochondrial fusion and fission. In particular, we will highlight specific mitochondrial insults caused by Aβ and tau in transgenic flies and will also discuss a variety of genetic tools and sensors available to study mitochondrial biology in this flexible organism. Areas of opportunity and future directions will be also considered.

Mitochondria in Alzheimer’s Disease Pathogenesis

“…Various animal and human studies have established the role of impaired mitophagy in AD [64]. Dysfunctional mitochondria lead to the accumulation of excess ROS and the depletion of ATP [65,66]. Impaired mitochondria at distal sites have to be transported to the soma for lysosomal degradation, and this retrograde transport may be impaired in AD [67,68].…”

Intrinsic determinants of prion protein neurotoxicity in Drosophila: from sequence to (dys)function

“…A class of brain disorders that have been studied extensively in flies are neurodegenerative diseases, in particular, those caused by progressive protein aggregation ( Surguchov, 2021 ; Nitta and Sugie, 2022 ; Santarelli et al, 2023 ; Varte et al, 2023 ). Between 1998 and 2001 several proteinopathies (three polyglutamines and tau) were modeled in flies for the first time, demonstrating that the proteins responsible for these conditions in humans preserve their toxic properties when expressed in flies ( Warrick et al, 1998 ; Fernandez-Funez et al, 2000 ; Kazemi-Esfarjani and Benzer, 2000 ; Wittmann et al, 2001 ).…”