News & Views: "Investigating the cellular phase of Alzheimer’s disease: the key for a cure?"


Prof Bart de Strooper and his group in Leuven, Belgium are performing cutting-edge research in the study of Alzheimer’s disease (AD). Prof De Strooper visited us from the Center for Brain and Disease Research at the University of Leuven to speak at our monthly GIGA conference series. During his lecture, Prof De Strooper discussed the increasing global prevalence of AD, which currently affects more than 35 million people and is predicted to affect up to 350 million people by the year 2050. In their lab, Prof De Strooper and his team are investigating the basic pathogenic mechanisms underlying AD and another neurodegenerative disease, Parkinson’s disease, starting with the genetic forms of these diseases. In addition, they collaborate with pharmaceutical companies in order to develop and test new drugs for these diseases [1].


AD is a neurodegenerative disorder typically characterized by a progressive loss of memory. At the cellular level, the pathological hallmarks of AD include neuritic plaques, which are formed by the accumulation of beta-amyloid proteins, and neurofibrillary tangles, which are composed of the abnormal aggregation of tau protein. Because current treatments focus on slowing the disease’s progression rather than healing the damaged brain tissue, it is extremely important to be able to develop an early marker to predict the disease and identify “at-risk” individuals.


To develop such a marker, Prof De Strooper and his team recently investigated the possible link between the enzyme phospholipase D3 (PLD3) and amyloid precursor protein (APP) suggested previously by Cruchaga et al. [2] Using a mouse model of AD, De Strooper’s team showed that PLD3 does not affect the expression of APP (Figure 1). As shown using western blot analysis, wild-type (ctrl) and Pld3 knockout (Pld3ko) express similar levels of APP. Interestingly, however, PLD3 was localised to lysosomes in the Pld3ko mice and appears to affect the cellular morphology (Figure 2) [3]. Because the lysosomal machinery is believed to play a role in the pathophysiology of AD [4], this may be the link between AD and PLD3.



Figure 1: Genetic deletion of Pld3 does not alter APP expression or processing. a, Western blot analysis of lysates from wild-type (Ctrl) and Pld3 knockout (Pld3ko) mice, showing the full-length (FL) APP and C-terminal fragment (CTF) of APP in the cortex of 3-month-old mice. b, Densitometry of western blot data (left). Adapted from Fazzari et al. [2].




Figure 2: Pld3 regulates the morphology of lysosomes in vivo. Shown are representative electron microscopy images of primary (top row, white arrowheads) and secondary (bottom row, black arrowheads) lysosomes in wild-type (Ctrl) and Pld3 knockout (Pld3ko) neurons. The white arrow indicates an electron-transparent inclusion in a secondary lysosome. Scale bars, 500 nm. Adapted from Fazzari et al. [2].


These new data challenge previous beliefs, and more research is clearly needed in order to fully understand the mechanistic link between AD and PLD3. Currently, however, to minimize the risk of AD and maximize patient outcome, Prof De Strooper recommends living a healthy lifestyle, obtaining an early diagnosis, and access to treatment, as well as the need to develop effective new drugs.




[2] Cruchaga, C. et al. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease. Nature 505, 550-554 (2014)

[3] Fazzari, P. et al. PLD3 gene and processing of APP. Nature 541, E1-E2 (2017)

[4] Nixon, R.A. The role of autophagy in neurodegenerative disease. Nat. Med. 19,

983-997 (2013).



Odile Bartholomé, PhD Student, GIGA-Neurosciences, Laboratory of Nervous System Disorders and Therapy

Adrien Lenelle, PhD Student, GIGA-Molecular Biology of Diseases, Laboratory of Cancer Signaling

Pamela Villar González, PhD Student, GIGA-CRC In vivo Imaging Memory and Aging Group



*This “News & Views” item was written as part of the course “Reading and understanding scientific literature and presentations” offered by GIGA Graduate School.