This blog post is about trying to understand what goes wrong in Alzheimer disease. I want to start the story 100 years ago…
In 1911 Thomas Morgan began the task of locating genes along the length of chromosomes. 100 years later, most of the DNA sequences for human chromosomes have been determined. One of the mutations reported by Morgan in 1911 was a wingless fruit fly. The human wnt-1 gene is homologous to Drosophila wingless and its position on chromosome 12 is shown here. WNT proteins are part of a conserved signal transduction pathway that is involved in the normal embryonic development of the nervous system. The WNT pathway might also play important roles in regulation of cell death in the adult nervous system (1).
When Darwin and Wallace started thinking about natural selection, nothing was known about how genetic instructions are stored inside cells. Around 1900 it was recognized that chromosomes behave like Mendelian units of inheritance. It became possible to start thinking about inheritance in terms of genes that are located at specific positions on chromosomes. After the double helix model of DNA structure was proposed, biologists began to think of genes in terms of sequences of nucleotide subunits along the length of chromosomes. In the 1970s there was a technical revolution based on the use of enzymes that can cut DNA at specific sequences. It became possible to clone and sequence specific genes.
100 years after Morgan’s report of wingless fruit flies, we can continue to harvest the fruits of the gene era in biology by exploring the hypothesis that the WNT pathway regulates cell survival in the brain (2). With luck, further study of genes like wnt will lead to a deeper understanding of Alzheimer disease. It has been suggested that disruption of normal Wnt signaling might play a role in neurodegeneration (3). Working with laboratory mice, it has been observed that lithium (4) and rosiglitazone (5) can have beneficial effects to protect against impairments of cognitive functions caused by expression of Alzheimer disease-causing APP gene. Lithium and rosiglitazone might have these beneficial effects by activating the Wnt signaling pathway. Similar results have been reported using Drosophila as an experimental system (6).
2017 review. Alzheimer Disease: Crosstalk between the Canonical Wnt/Beta-Catenin Pathway and PPARs Alpha and Gamma
i) NIH State-of-the-Science Conference Statement: Preventing Alzheimer’s Disease and Cognitive Decline.
ii) The prevention and treatment of cognitive decline and dementia: An overview of recent research on experimental treatments
iii) A roadmap for the prevention of dementia (list of related commentaries)
iv) Deciphering the function of canonical Wnt signals in development and disease: conditional loss- and gain-of-function mutations of beta-catenin in mice
v) Association of GSK3B With Alzheimer Disease and Frontotemporal Dementia