CELL has published the results of a collaboration between Rudy Tanzi, PH.D. and Huda Zoghbi, M.D. The work shows that a rare gene associated with an increased risk of Alzheimer’s, ATXN1, regulates an increase in BACE1, an enzyme that contributes to amyloid plaque accumulation.
Neurodegenerative disorders tend to fall into two distinct categories that are not thought of as overlapping: those that affect movement, called ataxias, and those that affect mental functioning, called dementias. ATXN1 is a rare Alzheimer’s associated gene that has been extensively studied in spinocerebellar ataxia type1 (SCA1), a neurodegenerative disorder. SCA1 has no known effective treatment or cure and can affect anyone at any age. In many cases, people are not aware that they carry a relevant gene until after they have children. An estimated 150,000 people are living with spinocerebellar ataxia in the United States and the average age of onset is in the forties. SCA1 symptomsvinclude the deterioration of motor coordination, balance, and progressive difficulty in swallowing and breathing in late stages. Impairments in verbal memory and frontal executive dysfunction also occur in later stages of the disease.
ATXN1 is a rare Alzheimer’s associated gene that has been studied in the neurodegenerative disorder, spinocerebellar ataxia type 1. Those who suffer from this disorder experience Alzheimer’s like dementia later in the progression of the disease. To test the hypothesis that ATXN1 might be involved in Alzheimer’s disease, the researchers used mice that were genetically modified to have the ATXN1 gene knocked out. The researchers were interested in determining whether the loss of ATXN1 would lead to biochemical changes that resembled the changes observed in the brain during Alzheimer’s disease. BACE1, the b-secretase enzyme that cleaves amyloid precursor protein and generates amyloid plaques, was increased by 45% in the ATXN1 knockout mice. These mice display impairments in learning in the hippocampus. This paper provides evidence that ATXN1 plays a role in learning and memory.
Prior to this study, there has been no evidence that any known candidate genes for Alzheimer’s disease could regulate BACE1 expression in the brain.
This paper is groundbreaking for its ability to demonstrate a unique regulatory mechanism by which ATXN1, a gene more commonly associated with motor neurodegeneration, can affect BACE1 levels. An increase in BACE1 expression can decrease neural precursor cell proliferation and negatively impact learning, memory, and the birth of new neurons. An interesting next direction for the field will be to determine how altering levels of amyloid precursor protein or BACE1 influences adult hippocampal neurogenesis – a process that is known to go awry in Alzheimer’s.