Findings suggests an alternative mechanism involved in familial Alzheimer’s disease
A study funded by the National Institutes of Health found evidence that neurodegeneration takes place even in the absence of beta-amyloid in mouse models of familial Alzheimer’s disease, which is caused by changes in PSEN genes that encode the protein presenilin. A research team from Harvard Medical School led by Jie Shen, Ph.D., removed beta-amyloid completely from mouse models and found no impact on age-dependent neurodegeneration. The results add to a body of work suggesting that PSEN variants may cause Alzheimer’s disease through loss of the protein’s essential function, rather than effects on beta-amyloid. The findings appear in the Proceedings of the National Academy of Sciences (PNAS).
Alzheimer’s disease is the most common neurodegenerative disorder, affecting more than 6 million Americans. In people with Alzheimer’s, abnormal levels of the beta-amyloid protein clump together to form plaques that slowly build up between neurons and are thought to prevent them from functioning properly.
While presenilin normally protects neurons, PSEN variants also increase the presence of toxic forms of beta-amyloid. These effects on beta-amyloid are cited as evidence for the “amyloid hypothesis”—the theory that abnormal accumulation of beta-amyloid proteins in the brain of persons with the presenilin mutation is a key contributor to their Alzheimer’s disease. Recently approved treatments for persons with early stage Alzheimer’s Disease clear beta-amyloid from the brain using antibodies made in the laboratory, called monoclonal antibodies, but the beneficial effects have been moderate.
However, the study findings challenge the conventional amyloid hypothesis in persons with a presenilin mutation and support an alternative theory called the presenilin hypothesis. The data indicate that presenilin gene variants—that cause what has traditionally been called familial Alzheimer’s disease—lead to age-related neurodegeneration that is unaffected by the presence (or absence) of beta-amyloid.
Presenilin normally helps generate beta-amyloid from amyloid-beta precursor protein (APP). It functions as a core protein in the enzyme complex called γ-secretase. When APP is cut by γ-secretase, it produces smaller pieces called beta-amyloid peptides, some of which can accumulate in the brain and form plaques. Presenilin also cuts other proteins that may be essential for brain health.
To test beta-amyloid’s role in familial Alzheimer’s disease, the research team looked at mice in which the most severe familial Alzheimer’s variant, called Psen1 L435F, was inserted or “knocked in” to the gene. They crossbred various presenilin mutant mice with those unable to produce APP. The team studied eight genotypic groups of mice at three ages (2, 12, and 18 months) and found that removing beta-amyloid through APP deficiency did not impact neurodegeneration. Even without beta-amyloid present, the mice still showed reduction of cortical volume and progressive loss of cortical neurons.
Additionally, lack of APP did not hinder cell death in the cerebral cortex of the mutant mice or microgliosis, a process whereby microglial cells activate and increase in number, often seen in Alzheimer’s and other diseases.
Together, the findings show that presenilin variants cause neurodegeneration independent of beta-amyloid, providing further support for a presenilin “loss of function” hypothesis. The study may have implications for treatment, as it suggests that removing beta-amyloid is unlikely to be effective for treating Alzheimer’s patients carrying PSEN variants.
This study was funded by the National Institute of Neurological Disorders and Stroke (NINDS) (R01NS041783) and National Institute on Aging (RF1AG063520).
Article:
Yan K. et al. “Cortical neurodegeneration caused by Psen1 mutations is independent of Aβ.” PNAS. August 14, 2024. DOI: 10.1073/pnas.2409343121.