Hippocampal neurons with staining for endosomes (turquoise and purple) and lysosomes (yellow). When the PSEN2 gene is absent or carries a familial Alzheimer-related mutation (center), the lysosomes turn into noticeably enlarged. Credit score: VIB
Alzheimer’s illness is a debilitating situation that slowly robs individuals of their reminiscence and cognitive skills, affecting thousands and thousands of individuals worldwide. Familial Alzheimer’s illness (FAD), a uncommon inherited type of the illness, is linked to mutations in a number of genes, together with APP, PSEN1, and PSEN2. The affect of PSEN2 mutations has remained much less understood—till now.
A analysis crew led by Prof. Wim Annaert at VIB-KU Leuven has make clear how mutated PSEN2 accelerates illness development in FAD.
Their findings, printed in Nature Communications, provide new insights into the mechanisms driving this genetic type of the illness. The paper is titled “Altered expression of Presenilin2 impacts endolysosomal homeostasis and synapse function in Alzheimer’s disease-relevant brain circuits.”
Alzheimer’s illness is characterised by the gradual lack of cognitive perform, reminiscence, and behavioral adjustments, with the mind displaying a build-up of amyloid plaques. These plaques kind after a protein referred to as APP (amyloid precursor protein) is “cut into pieces” by, amongst others, the γ-secretase advanced.
A few of these items are β-amyloid (Aβ) peptides, which might clump collectively to kind the dangerous plaques. The γ-secretase advanced exists in several variants, containing both PSEN1 or PSEN2, which truly impacts its location inside the cell, hinting at refined useful variations between the 2.
Mutations within the genes encoding these functionally associated proteins could cause FAD, an inherited type of Alzheimer’s that sometimes develops sooner than the extra widespread late-onset model, with signs typically beginning as early as an individual’s 30s or 40s.
Though it’s identified that poisonous Aβ fragments construct up early in FAD and contribute to mind harm, the particular mechanisms by which PSEN2 mutations speed up this course of weren’t absolutely understood. The lab of Prof. Annaert on the VIB-KU Leuven Middle for Mind & Illness Analysis in contrast the results of a lack of PSEN2 with these of a mutant type of the PSEN2 gene to know how illness develops in these FAD instances.
A double-edged knife
The analysis crew studied the results of PSEN2 loss and an FAD-linked mutation in mouse fashions mimicking Alzheimer’s illness. Each the absence of PSEN2 and the presence of mutated PSEN2 led to quicker accumulation of amyloid plaques within the mind. Furthermore, the mice with no or mutated PSEN2 each exhibited important reminiscence impairments.
These impairments correlated with structural and useful adjustments within the hippocampus, a key space for working reminiscence that’s primarily affected in AD sufferers. This mind space is important for duties like remembering instructions whereas driving or strolling, or following multi-step directions, akin to cooking recipes.
Constantly, the researchers noticed that lacking or impaired PSEN2 harmed the functioning of synapses—the connections between mind cells that permit them to speak. The power of synapses to strengthen over time, a course of referred to as long-term potentiation, was impaired as nicely, which negatively impacts studying and reminiscence.
To uncover the origin of those impairments, the crew investigated mechanisms inside essential mind cells—neurons. They discovered that PSEN2 performs a crucial function in sustaining wholesome mobile processes inside late endosomes and lysosomes—the cells’ “garbage disposal system” that breaks down and recycles proteins.
A misplaced or mutated PSEN2 gene disrupted these processes, inflicting a poisonous build-up of APP fragments inside, together with Aβ peptides. So not solely does impairment of the PSEN2 gene result in extra poisonous amyloid plaques, it additionally results in a degradative bottleneck inside nerve cells, inflicting defects within the recycling of different molecules, together with these which are answerable for transmitting alerts between nerve cells.
“These results highlight the multi-faceted impact of PSEN2 mutations—on one hand, driving toxic amyloid accumulation, and on the other, impairing fundamental cellular maintenance systems, amplifying synaptic and cognitive decline,” says Anika Perdok, first creator of the paper.
What this implies for Alzheimer’s analysis
Prof. Annaert emphasizes, “Our findings underscore the significance of PSEN2 in regulating mind cell well being. Concentrating on the underlying mobile dysfunction brought on by PSEN2 mutations might be a possible route for Alzheimer’s therapies.
“To translate these insights into treatments, we require further research, but our work suggests that therapies aimed at restoring the function of endosomes and lysosomes or normalizing γ-secretase activity in these organelles could help mitigate the effects of PSEN2 mutations and slow disease progression in FAD.”
Extra info:
Anika Perdok et al, Altered expression of Presenilin2 impacts endolysosomal homeostasis and synapse perform in Alzheimer’s disease-relevant mind circuits, Nature Communications (2024). DOI: 10.1038/s41467-024-54777-y
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VIB (the Flanders Institute for Biotechnology)
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Understanding the genetic roots of uncommon mutations in Alzheimer’s illness (2024, December 3)
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