Protein Offers Commonality To Alzheimer’s Disease And Neurovascular Dysfunction


Researchers from the University of Torino in Italy have correlated a protein to two major pathways affecting Alzheimer’s disease progression. The research group found that a brain protein, ubiquitin C-terminal hydrolase L1 (Uch-L1), is able to reduce the production of amyloid beta plaques and neurovascular dysfunction.

A common co-pathology of Alzheimer’s disease is the presence of neurovascular dysfunction, or vascular dementia, termed as mixed-dementia.

Uch-L1 protein expression is commonly reduced in Alzheimer’s disease brains. The research group used animal models of Alzheimer’s disease gene expression and surgically induced neurovascular injury to mimic the disease in the lab.

Their experiments showed that both neurovascular injury and the Alzheimer’s disease gene expression reduced Uch-L1 production; resulting in increased cell death in both conditions. They established a link between the reductions of Uch-L1 increased expression of beta secretase-1 (BACE1), a protein which forms the toxic amyloid beta.

Uch-L1 Restoration Protects Cells

Through restoring the activity of Uch-L1 the group were able to observe an inhibition of BACE1 protein production and also a protective effect on cells, with a significant reduction in cell death. Previous studies have shown that the increase of BACE1 is activated through the NF-B pathway, and this NF-B activity also decreases Uch-L1 levels.

In this study the group established that neurovascular damage was capable of inducing increased NF-B levels. This has led the authors to suggest that this neurovascular dysfunction could be responsible for the depletion of Uch-L1.

Alzheimer’s Disease Complexity

The identification of this protein which could inhibit disease progression from two separate pathways could offer a more effective target for Alzheimer’s disease therapies.

Alzheimer’s disease is a complex neurodegenerative condition, with multiple different pathways that contribute to the characteristic degradation of brain tissue.

The complexity of the disease has made it hard to treat. Drugs which affect one pathway can be ineffective at treating another, leaving the disease free to progress relatively uninhibited.

The current licensed treatments primarily consist of drugs which treat only the symptoms of Alzheimer’s disease, not the pathological degeneration of the brain.

Dual-Hit Hypothesis

The ‘dual-hit hypothesis’ of Alzheimer’s disease indicates that there are both neural and vascular dysfunctions which contribute to the onset and progression of the disease. Multiple studies have observed an increased severity of dementia from the presence of neurovascular dysfunction, with co-existence of causing a dramatic decrease in cognitive capacity.

The increased build-up of toxic proteins characteristic of Alzheimer’s disease can be intensified by vascular dysfunction, due to reduced clearance through the blood. In addition, neurovascular dysfunction leads to increased neuroinflammation through an increased permeability across the blood-brain barrier; allowing for immune cells and foreign blood elements to enter the brain.

Therapeutic Potential

The targeting of Uch-L1 (either directly or indirectly) could offer a novel mechanism to combat both Alzheimer’s disease and vascular dementia.

The continued failure of multiple drug trials for Alzheimer’s disease have led to the focus of treatment being shifted from the archetypal ‘amyloid hypothesis’ to drugs which may be able to treat the associated neurovascular dysfunction. The data presented by the authors leads them to suggest that restoration of Uch-L1 activity could offer a novel therapeutic strategy for both Alzheimer’s disease and vascular dementia.

Michela Guglielmotto, Debora Monteleone, Valeria Vasciaveo, Ivan Enrico Repetto, Giusi Manassero, Massimo Tabaton and Elena Tamagno
The Decrease of Uch-L1 Activity Is a Common Mechanism Responsible for A 42 Accumulation in Alzheimer’s and Vascular Disease
Frontiers in Aging Neuroscience: 29 September 2017. doi: 10.3389/fnagi.2017.00320

Last Updated on November 12, 2022