Alzheimer’s disease is a progressive condition that impairs memory and cognitive function, affecting millions globally. Familial Alzheimer’s disease (FAD), a rare inherited form, is associated with mutations in genes like APP, PSEN1, and PSEN2.
While the role of PSEN2 mutations was not well understood, a research team led by Prof. Wim Annaert at VIB-KU Leuven has discovered how mutated PSEN2 accelerates disease progression in FAD, providing new insights into its impact.
Alzheimer’s disease is marked by a gradual decline in cognitive function, memory, and behavior, with amyloid plaques accumulating in the brain. These plaques form when the amyloid precursor protein (APP) is cleaved by the γ-secretase complex, generating β-amyloid (Aβ) peptides that can aggregate into harmful plaques.
The γ-secretase complex includes variants containing either PSEN1 or PSEN2, influencing its cellular location and suggesting subtle functional differences. Mutations in the genes encoding these proteins can lead to familial Alzheimer’s disease (FAD), an inherited form that typically has an earlier onset, with symptoms appearing in a person’s 30s or 40s, unlike the more common late-onset form.
While it is known that toxic Aβ fragments accumulate early in familial Alzheimer’s disease (FAD) and contribute to brain damage, the exact mechanisms by which PSEN2 mutations accelerate this process are unclear.
To investigate, Prof. Wim Annaert’s lab at the VIB-KU Leuven Center for Brain & Disease Research compared the effects of a loss of PSEN2 with those of a mutant form of the PSEN2 gene. This comparison aimed to understand better how these mutations drive disease progression in FAD cases.
The research team investigated the effects of PSEN2 loss and an FAD-linked PSEN2 mutation in mouse models of Alzheimer’s disease. They found that the absence of PSEN2 and the presence of mutated PSEN2 accelerated amyloid plaque accumulation in the brain.
Additionally, these mice exhibited significant memory impairments linked to structural and functional changes in the hippocampus, a brain region crucial for working memory and commonly affected in Alzheimer’s patients.
This area involves tasks such as remembering directions or following complex instructions. The researchers also observed that the lack or mutation of PSEN2 disrupted synaptic function—the connections between brain cells—and impaired long-term potentiation, a process essential for learning and memory.
To understand the source of the impairments, the research team examined the mechanisms within neurons, the brain cells affected by Alzheimer’s disease. They discovered that PSEN2 is crucial in maintaining proper cellular functions within late endosomes and lysosomes, the cell’s “garbage disposal system” for breaking down and recycling proteins.
When the PSEN2 gene is lost or mutated, this process is disrupted, leading to a toxic accumulation of APP fragments, including Aβ peptides. This results in more harmful amyloid plaques and creates a degradative bottleneck within nerve cells, impairing the recycling of essential molecules, including those involved in neurotransmission and communication between nerve cells.
Anika Perdok, the first author of the paper, said, “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.”
Prof. Wim Annaert emphasizes: “Our findings underscore the importance of PSEN2 in regulating brain cell health. Targeting the underlying cellular dysfunction caused by PSEN2 mutations could be a potential route for Alzheimer’s treatments.”
“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.”
Journal Reference:
- Perdok, A., Van Acker, Z.P., Vrancx, C. et al. Altered expression of Presenilin2 impacts endolysosomal homeostasis and synapse function in Alzheimer’s disease-relevant brain circuits. Nat Commun 15, 10412 (2024). DOI: 10.1038/s41467-024-54777-y