Per Nilsson group

The role of autophagy in Aβ metabolism and neurodegeneration in Alzheimer’s disease

Research focus

Alzheimer’s disease (AD) is characterized by changes in protein homeostasis which leads to accumulation and aggregation of proteins that are toxic to cells in the brain. In AD, these include amyloid beta peptide (Aβ) and tau protein. Autophagy is a master regulator of proteostasis which maintain and adjust the proteome depending on the environment of the cell. This ensures that misfolded and potentially toxic proteins are degraded and at the same time refill the pool of amino acids that will serve as source for the for synthesis of novel proteins. Autophagy is malfunctioning in the Alzheimer’s disease brain and may therefore contribute to the disease progression.

We are analyzing the mechanism of autophagy in the metabolism of Aβ using state of the art AD mouse models. Using genetic tools, we inhibit autophagy in different neuronal cells. Intriguingly, we have found that when autophagy is deleted in the nerve cells, the extracellular Aβ plaques decrease and Aβ instead accumulates intracellularly. This activates neurodegenerative processes which could be linked to the neurodegeneration taking place in the AD brain. This neurodegeneration is currently being investigated by different genetic and omics approaches.

Aβ levels are increased in both familiar and sporadic AD. In familiar AD, genetic mutations cause the increase in Aβ while in sporadic AD a decreased degradation of Aβ may explain the augmented levels. Neprilysin is the major Aβ-degrading enzyme which is controlled by somatostatin receptor (SSTR) signaling. Our aim is to identify blood-brain-barrier-permeable SSTR agonists that activates neprilysin in high through put screens to lower Ab levels.

Group members

Per Nilsson

Principal researcher

Richeng Jiang

Affiliated to research

Simone Tambaro

Senior research specialist

Erika Bereczki

Research specialist

Makoto Shimozawa

Assistant professor

Johanna Mayer

PhD student

Hao Li

PhD Student

Jack Lloyd Badman

Postdoctoral researcher

Selected publications

Translational potential of synaptic alterations in Alzheimer's disease patients and amyloid precursor protein knock-in mice.
Medina-Vera D, Enache D, Tambaro S, Abuhashish E, Rosell-Valle C, Winblad B, Rodríguez de Fonseca F, Bereczki E, Nilsson P
Brain Commun 2023 ;5(1):fcad001

Autophagy Impairment in App Knock-in Alzheimer's Model Mice.
Jiang R, Shimozawa M, Mayer J, Tambaro S, Kumar R, Abelein A, Winblad B, Bogdanovic N, Nilsson P
Front Aging Neurosci 2022 ;14():878303

Increased CSF-decorin predicts brain pathological changes driven by Alzheimer's Aβ amyloidosis.
Jiang R, Smailovic U, Haytural H, Tijms BM, Li H, Haret RM, Shevchenko G, Chen G, Abelein A, Gobom J, Frykman S, Sekiguchi M, Fujioka R, Watamura N, Sasaguri H, Nyström S, Hammarström P, Saido TC, Jelic V, Syvänen S, Zetterberg H, Winblad B, Bergquist J, Visser PJ, Nilsson P
Acta Neuropathol Commun 2022 07;10(1):96

Targeting Alzheimer's disease with gene and cell therapies.
Loera-Valencia R, Piras A, Ismail M, Manchanda S, Eyjolfsdottir H, Saido T, et al
J. Intern. Med. 2018 Jul;284(1):2-36

Loss of neprilysin alters protein expression in the brain of Alzheimer's disease model mice.
Nilsson P, Loganathan K, Sekiguchi M, Winblad B, Iwata N, Saido T, et al
Proteomics 2015 Oct;15(19):3349-55

Autophagy-related protein 7 deficiency in amyloid β (Aβ) precursor protein transgenic mice decreases Aβ in the multivesicular bodies and induces Aβ accumulation in the Golgi.
Nilsson P, Sekiguchi M, Akagi T, Izumi S, Komori T, Hui K, et al
Am. J. Pathol. 2015 Feb;185(2):305-13

Single App knock-in mouse models of Alzheimer's disease.
Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, et al
Nat. Neurosci. 2014 May;17(5):661-3

New mouse model of Alzheimer's.
Nilsson P, Saito T, Saido T
ACS Chem Neurosci 2014 Jul;5(7):499-502

Aβ secretion and plaque formation depend on autophagy.
Nilsson P, Loganathan K, Sekiguchi M, Matsuba Y, Hui K, Tsubuki S, et al
Cell Rep 2013 Oct;5(1):61-9

Content reviewer:
Philipp Kreft