Perdok A, Van Acker ZP, Vrancx C, Sannerud R, Vorsters I, Verrengia A, Callaerts-Végh Z, Creemers E, Gutiérrez Fernández S, D'hauw B, Serneels L, Wierda K, Chávez-Gutiérrez L, Annaert W. Altered expression of Presenilin2 impacts endolysosomal homeostasis and synapse function in Alzheimer's disease-relevant brain circuits. Nat Commun. 2024 Nov 29;15(1):10412. PubMed.
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Columbia University
This manuscript directly addresses two important, but related, questions that are actively, and sometimes heatedly, discussed in meetings.
1. The neurodegenerative process is the direct driver of brain dysfunction and the disease’s debilitating symptoms. So, is it AD’s extracellular pathology (amyloid plaques) or intracellular pathology (endolysosomal disruption) that is the primary driver of neurodegeneration? Is the trigger inside or outside the neuron?
The paper provides additional evidence that PSEN2, like the other causal AD mutations in APP, PSEN1, and SORL1, causes intraneuronal endolysosomal pathology independent of extracellular amyloid pathology. It then elegantly explains the neurobiology of how this intracellular pathology leads to profound synaptic dysfunction, independent of extracellular pathology. This aspect of the manuscript is, therefore, generally supportive of the view that it is the intracellular pathology that might trigger the neurodegenerative process, and might explain why clearing plaques in patients has, thus far, shown little amelioration of neurodegeneration. I say, “thus far,” since I am hoping that for my patients we will see benefits on neurodegenerative readouts and stronger benefits on clinical readouts when the drugs are tested in earlier stages of disease.
2. Even if endolysosomal disruptions are the trigger, the problem then is to reconcile that many neurodegenerative diseases target the same intracellular system, as we are becoming increasingly aware. The solution might be that neurodegenerative disorders differentially target separate components of the endolysosomal network, which after all is comprised of multiple molecularly and functionally distinct organelles and endowed with multiple trafficking routes. So, which specific component of the endolysosomal network is differentially targeted by AD?
While having many effects, the paper localizes PSEN2’s main effect to a specific endosomal pathway required for the normal recycling of glutamate receptors to the post-synaptic neuronal surface. In fact, there are numerous endosomal recycling pathways, and so the paper can be even more precise: It is specifically the retromer-dependent recycling pathway that regulates glutamate receptor recycling. The idea that AD, compared to other neurodegenerative disorders, differentially targets this specific pathway is supported by other causal genes, notably, SORL1, and maybe even APP (see for example Chen et al., 2023).
References:
Chen XQ, Sawa M, Becker A, Karachentsev D, Zuo X, Rynearson KD, Tanzi RE, Mobley WC. Retromer Proteins Reduced in Down Syndrome and the Dp16 Model: Impact of APP Dose and Preclinical Studies of a γ-Secretase Modulator. Ann Neurol. 2023 Aug;94(2):245-258. Epub 2023 Apr 29 PubMed.
View all comments by Scott SmallLund University
This is another high-level study by the Annaert lab and collaborating groups in Leuven, providing numerous novel insights into how presenilin 2 (PSEN2) KO and a common familial AD PSEN2 mutation affect synapses/physiology, dystrophic neurites/plaques, endolysosomes, and behavior when crossed with, and compared to, the APP NL-G-F KI mouse model of AD. They describe intriguing differences between PSEN2 KO and the PSEN2 FAD mutation. Such comprehensive studies in experimental AD research that encompass many diverse methods to provide new synaptic-cellular mechanistic insights are rare in our field.
Many questions arise from this excellent work. We are given intriguing insights into the synaptic functions of PSEN2. Remarkably, PSEN2 KO worsens amyloid pathology in the APP KI mice, which is ascribed to the increased ability of PSEN1 to secrete Aβ in the setting of PSEN2 KO. The PSEN2 FAD mutation causes elevated intracellular Aβ. PSEN2 KO is not clearly linked with human AD, while FAD PSEN1 and 2 mutations of course both induce AD pathogenesis. It remains unclear why PSEN1 and 2 mutations seem to similarly induce AD pathology when they have different effects on intra- and extra-pools of Aβ, although they both do lead to longer Aβ peptides.
View all comments by Gunnar GourasNOVA Medical School
The PSEN2 mutation is associated with familial early onset Alzheimer’s disease and is predicted to be pathogenic, supported by evidence from transgenic animals. Previous work from Win Annaert nicely tied PSEN2 activity to late endosomes and production of intracellular Aβ42. These data relate to our initial observations that late endosomes become dysfunctional due to accumulation of Aβ42 in endosomes (Almeida et al. 2006).
In this latest excellent paper, the Annaert and Gutierrez labs show that crossing a knock-in of the most common PSEN2 mutation, N141K, with a KI of three human APP familial mutations aggravates the AD-like phenotype, proving causality. The mice recapitulate aggravated amyloidosis and memory deficits, likely due to the PSEN2 loss of function in synapses and the endolysosomal system, as the PSEN2 KO phenotype is similar.
One wonders about the relative contribution of the PSEN2 mutation to endolysosome and synapse dysfunction, whether via a direct effect of PSEN2 function or via Aβ production. It would be interesting to investigate whether improving endolysosomal function, as we did in aged neurons (Burrinha et al. 2023), recovers synapses.
This excellent manuscript builds on the proposal by us and others that rescuing the endolysosomal system would be an exciting therapeutic target with the potential to treat Alzheimer’s disease—at least for carriers of PSEN2 mutations. Further work should be undertaken in this direction.
References:
Almeida CG, Takahashi RH, Gouras GK. Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system. J Neurosci. 2006 Apr 19;26(16):4277-88. PubMed.
Burrinha T, Cunha C, Hall MJ, Lopes-da-Silva M, Seabra MC, Guimas Almeida C. Deacidification of endolysosomes by neuronal aging drives synapse loss. Traffic. 2023 Aug;24(8):334-354. Epub 2023 May 23 PubMed.
View all comments by Claudia AlmeidaThe University of Tokyo
In this study, the authors examined the pathological significance of PSEN2 in a mouse model of AD: APP knock-in mice, in which Aβ plaques accumulate, were crossed with a PSEN2 knockout or with mice that had the PSEN2 familial AD mutation, N141I, knocked in, to examine effects on Aβ production and Aβ plaque accumulation.
Interestingly, the deposition of Aβ plaques was exacerbated in PSEN2 N141I knock-in and PSEN2 knockout mice, indicating that inhibition of γ-secretase activity of PSEN2 leads to worsening Aβ pathology. At the same time, synaptic, endolysosomal, and behavioral abnormalities were observed in these mice, indicating that partial inhibition of PSEN2 exacerbates AD pathology.
The study elucidated that various functional abnormalities of PSEN are involved in AD pathophysiology. Moreover, this is an important paper in that it demonstrates the unprecedented concept that changes in PSEN2 expression may affect the process of AD pathogenesis in vivo.
View all comments by Taisuke TomitaMake a Comment
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