PSEN1 Mutations Trigger Brain Degeneration Independent of Beta-Amyloid
Post by Soumilee Chaudhuri
The takeaway
Mutations in the presenilin 1 (PSEN1) gene are a major cause of familial Alzheimer’s disease, commonly known as early-onset Alzheimer’s Disease (EOAD), which affects individuals below the age of 65. This study discovered that PSEN1 mutations can lead to neurodegeneration in the brain through pathways that do not involve Amyloid-beta (Aβ) accumulation — a well-known hallmark and the most commonly studied therapeutic target of AD.
What's the science?
PSEN1 is part of γ-secretase, an enzyme that instructs precursor proteins like amyloid precursor protein (APP) to produce amyloid-beta (Aβ) peptides, which cause AD. Over 450 mutations in the PSEN gene have been linked to AD and while PSEN1 helps protect neurons, its mutations increase the ratio of the harmful and mutated Aβ (Aβ42) to non-mutated Aβ peptide (Aβ40) levels. Therefore, it's unclear whether these PSEN1 gene mutations cause AD by increasing the harmful Aβ42/ Aβ42 ratio or impairing the gene's protective functions. This week in PNAS, Yan and colleagues investigated whether a specific PSEN1 mutation (PSEN1 L435F), a severe familial AD mutation, causes age-related neurodegeneration independently of Aβ.
How did they do it?
The researchers engineered a mouse model carrying the PSEN1 L435F mutation, associated with EOAD, and bred it with mice lacking the amyloid precursor protein (APP) to reduce Aβ production in the offspring mice. Mice of both sexes, aged 2, 12, and 18 months old were used in this experiment, and detailed analyses of their brain tissue post-mortem allowed for the measurement of cortical atrophy, neuron loss, and other signs of neurodegeneration. Additionally, they also worked with several other mouse models that specifically deleted PSEN1 genes in brain cells. This setup allowed the researchers to investigate how these genetic changes impact neurodegeneration across different ages and different strains of mice all containing the PSEN1 mutation but lacking APP.
What did they find?
The researchers found that even with the APP deletion and Aβ absent, mice with the PSEN1 L435F mutation still developed significant cortical neurodegeneration, similar to that seen in AD in humans. The researchers also noted increased cell death and brain inflammation. Even with no Aβ production, these mice still experienced significant cortical volume reduction, neuron loss, increased cell death, and brain inflammation at all ages (2, 12, and 18 months). This suggests that the neurodegenerative processes in these mice are driven by alternative, non-amyloid pathways.
What's the impact?
Mice with PSEN1 mutations exhibited severe neurodegeneration, synaptic impairment, and memory deficits, independent of amyloid beta levels. These findings challenge the amyloid-centric model of Alzheimer’s disease, particularly in cases involving PSEN1 mutations. Understanding these non-amyloid pathways could open up new avenues for treating Alzheimer’s by targeting alternative mechanisms of neurodegeneration. Despite extensive anti-Aβ therapeutic efforts, such as the approval of lecanemab, clinical outcomes have been modest. These findings emphasize the need for a broader understanding of AD, including the role of PSEN1 function, to develop more effective therapies.