The Cellular Phase of Alzheimer’s Disease
De Strooper B, Karran E. The Cellular Phase of Alzheimer’s Disease. Cell. 2016 Feb 11;164(4):603-15. doi: 10.1016/j.cell.2015.12.056. PMID: 26871627.
The linearity of the cascade remains very controversial. For instance, exploration of the direct link between Aβ and neurotoxicity has resulted in a rather confusing literature with at least ten different molecular mechanisms and receptors (see Figure 1) (Benilova et al., 2012). It is debatable whether they all equally contribute to the disease process in humans, as many of the supporting studies used non-physiologically high concentrations of Aβ or transgenic mice significantly overexpressing APP Thus, the neuron-centric view has to be expanded to one that considers the contribution of different cell types, their interactions with each other, and the gradual evolution of the disease.
Instead of Aβ and Tau, the real causes of sporadic disease are upstream of these proteopathies and are likely manifold, with aging being the major driver.
This paper examines the amyloid cascade hypothesis and questions the linearity of the amyloid cascade in producing AD pathology, saying the biochemistry of the brain needs to be intergrated. They found that studies supporting the amyloid cascade hypothesis used non-physiologically high concentrations of Aβ or transgenic mice overexpressing APP. Since a lot of ‘confusing’ literature with many different molecular mechanisms have come out they are skeptical that all equally contribute to AD pathology. They also suggested that instead of Aβ and tau, the real causes of sporadic disease may be upstream of those proteopathies, with aging being the major driver of these conditions.
In general, they believe that the neuron-centric view needs to be expanded to consider the contribution of different cell types and interactions including astrocytes, microglia, oligodendrocytes, and the role of the neurovascular unit and the vascular hypothesis of AD. With single-cell sequencing, more of these mechanisms and pathways can be explored.
They also suggested that instead of Aβ and tau, the real causes of sporadic disease may be upstream of those proteopathies, with aging being the major driver of these conditions.