A new hypothesis of Alzheimer's disease etiology

What is it about?

Alzheimer’s disease affects nearly half of cellular metabolic pathways, so a new hypothesis of Alzheimer’s initiation and progression (etiology) was developed using a systems biology approach (i.e., looking at many pathways affected rather than just tau or amyloid-beta involvement). The idea is to identify events occurring prior to tau and amyloid-beta abnormalities. Also, since Alzheimer’s is a neurodegenerative AND an autoimmune disease, autoimmune disease tautology was explored. Autoimmune disease tautology refers to common features among the many autoimmune diseases, such as female predominance, mid- to late adult onset, greater severity with earlier onset, and polyautoimmunity (more than one autoimmune disease in a single patient). So, for example, Sjögren’s syndrome can occur concurrently in patients who have lupus, Alzheimer’s, rheumatoid arthritis, multiple sclerosis, or Parkinson’s disease. The hypothesis was developed using online search engines (e.g., PubMed) with combinations of key words (e.g., Alzheimer’s, lupus, nucleolin, polyamines, and more). This revealed synergistic insights from other diseases that could apply to Alzheimer’s disease cellular events. Polyamines are small positively charged molecules with many important functions in cells, particularly in the nucleolus where many cell components are made. Under cellular stress (e.g., viral activity), polyamines increase and cause expansion of the nucleolus. Abnormal expansion can disrupt epigenetics (gene expression control) on peri-nucleolar chromosomes. Some of the genes near the nucleolus that can be affected are presenilin-1 (chromosome 14) involved in amyloid processing, tau (chromosome 17) involved in microtubule formation, amyloid precursor protein (chromosome 21), apoE4 (chromosome 19) involved in amyloid deposition, and polyamine synthesis and recycling genes (inactive X chromosome). Extraordinary synthesis of polyamines can lead to phosphorylation of tau and subsequent aggregation with polyamines. Increased recycling of polyamines can reduce acetyl-CoA needed for synthesis of the neurotransmitter acetylcholine, which is low in Alzheimer’s disease. In addition, disruption of chromosomes can open the abundance of Alu pseudo-genes (greater than one million copies in the human genome). Abnormal expression of Alu elements can lead to loss of integrity of the nucleolus and eventual cell death.

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Why is it important?

This hypothesis identifies several potential therapeutic targets for interdiction earlier in Alzheimer's disease. This could slow and possibly reduce the consequences of the disease.

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