American researchers have discovered a previously unknown cellular mechanism that may trigger the development of Alzheimer's disease. The discovery helps explain why the risk of the disease sharply increases with age and why some people are genetically more vulnerable to dementia.
A cellular mechanism capable of triggering the formation of pathological tau protein clumps—structures associated with memory loss and neuronal death—may underlie the development of Alzheimer's disease. This conclusion was reached by scientists who reproduced their formation in the brains of mice.
Alzheimer's disease is traditionally linked to the accumulation of amyloid protein plaques and tau protein clumps in brain tissue. However, in recent years, numerous studies have shown that it is the accumulations of tau protein that correlate better with the deterioration of memory and cognitive functions. It has been found that in the brains of patients, tau protein forms paired helical filaments (PHF), which then assemble into neurofibrillary tangles (NFT). However, it was unclear to scientists what exactly underlies the transition of normal tau protein into its pathological form.
Now, a research group from Columbia University (USA) has discovered that a special protein quality control system, which is present only in neurons, may play a leading role in triggering Alzheimer's disease. This structure has been named the "neuroproteasome."
To clarify: the regular proteasome acts as a cellular waste disposal system, breaking down damaged or unnecessary proteins. Several years ago, an additional variant of it was discovered in neurons. Neuroproteasomes are located directly on the outer membrane of nerve cells and specialize in destroying recently synthesized proteins that are particularly prone to misfolding.
To investigate the function of this unusual structure, neurobiologists developed tools to selectively block the activity of neuroproteasomes. As a result, shortly after suppressing their activity, PHF began to form in the neurons. Moreover, in terms of their biochemical properties and microscopic structure, they were very similar to those found in the brains of patients with Alzheimer's disease.
Experiments were conducted both on neuron cultures and on mice. In all cases, the disruption of neuroproteasome function led to the spontaneous formation of pathological tau protein accumulations. This is important because most existing models of Alzheimer's disease are based on artificially "infecting" animals with human PHF and other pathological forms of tau protein obtained from patient tissues or grown in the laboratory. This hampers the study of the very early stages of the disease's development.
The researchers paid special attention to the APOE gene—the largest known genetic risk factor for the disease. The gene exists in three main variants: APOE2, APOE3, and APOE4, which encode different forms of the ApoE protein. Carriers of APOE4 have a significantly higher risk of developing the pathology, while the APOE2 variant is considered protective.
It was found that different forms of the ApoE protein affect the number of neuroproteasomes on the surface of neurons differently. The highest number was observed in ApoE2 carriers, an intermediate number in ApoE3, and the lowest in ApoE4. For this reason, neurons with the APOE4 gene variant were more vulnerable to disruptions in the protein disposal system and began to accumulate pathological forms of tau protein more quickly.
This pattern was confirmed by further analysis of human brain tissues. In individuals with two copies of APOE4, the number of neuroproteasomes was much lower than in carriers of other gene variants. Additionally, it was found that the number of neuroproteasomes gradually decreased with age. Since aging remains the main risk factor, the results help explain why the likelihood of developing the disease sharply increases in old age.
Thus, the scientists linked two important factors of the disease—aging and APOE4—into a single picture. Their model showed that age-related decreases in the number of neuroproteasomes and the genetically determined deficiency of these structures weaken the quality control over proteins in neurons. As a result, the likelihood of misfolding tau protein increases, triggering the process of PHF formation characteristic of Alzheimer's disease.
The results of the study allow for a new perspective on the causes of Alzheimer's disease. The researchers managed to connect two key risk factors—aging and the APOE4 gene—through the functioning of a special system for clearing neurons of defective proteins. If further research confirms these findings, neuroproteasomes may become a promising target for developing new methods for the prevention and treatment of one of the most common neurodegenerative diseases.
