The amyloid cascade hypothesis is the earliest coherent view of the development of Alzheimer’s disease. In this view, the condition begins with the slow aggregation of amyloid-β over many years, and this process sets up the cell dysfunction and chronic inflammation that allows much more harmful later stage of tau aggregation to get underway in earnest. This hypothesis has dominated research and development for many years, and across this period of time, alternative views and approaches to the condition gained little traction and funding.
Therapies based on clearance on amyloid-β took a long time to achieve the goal of reducing amyloid-β levels in humans. This was only demonstrated in the past few years, and, unfortunately, failed to produce meaningful patient benefits. This has led to considerable unrest and rebellion against the consensus in the Alzheimer’s research community. There is a great deal of renewed theorizing, and new directions in the development of therapies are finally seeing greater funding and attention.
One important new direction is the clearance of senescent supporting cells from the brain. Animal data strongly suggests that senescent microglia and astrocytes are causing considerable harm in the aging brain, and are particularly important in Alzheimer’s disease. One of the early senolytic drugs, dasatinib, can pass the blood-brain barrier to selectively destroy senescent cells in the brain. It has been used to reverse neurodegeneration and neuroinflammation in animal models of Alzheimer’s disease. Is it the case that amyloid-β accumulation creates a greater burden of cellular senescence in old age, and once a significant senescent cell population is established, it doesn’t much help to remove the amyloid-β? Maybe so.
Due to their postmitotic status, the potential for neurons to undergo senescence has historically received little attention. This lack of attention has extended to some non-postmitotic cells as well. Recently, the study of senescence within the central nervous system (CNS) has begun to emerge as a new etiological framework for neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD).
The presence of senescent cells is known to be deleterious to non-senescent neighboring cells via development of a senescence-associated secretory phenotype (SASP) which includes the release of inflammatory, oxidative, mitogenic, and matrix-degrading factors. Senescence and the SASP have recently been hailed as an alternative to the amyloid cascade hypothesis and the selective killing of senescence cells by senolytic drugs as a substitute for amyloid beta (Aß) targeting antibodies.
Here we call for caution in rejecting the amyloid cascade hypothesis and to the dismissal of Aß antibody intervention at least in early disease stages, as Aß oligomers (AßO), and cellular senescence may be inextricably linked. We will review literature that portrays AßO as a stressor capable of inducing senescence. We will discuss research on the potential role of secondary senescence, a process by which senescent cells induce senescence in neighboring cells, in disease progression. Once this seed of senescent cells is present, the elimination of senescence-inducing stressors like Aß would likely be ineffective in abrogating the spread of senescence. This has potential implications for when and why AßO clearance may or may not be effective as a therapeutic for AD.
The selective killing of senescent cells by the immune system via immune surveillance naturally curtails the SASP and secondary senescence outside the CNS. Immune privilege restricts the access of peripheral immune cells to the brain parenchyma, making the brain a safe harbor for the spread of senescence and the SASP. However, an increasingly leaky blood brain barrier (BBB) compromises immune privilege in aging AD patients, potentially enabling immune infiltration that could have detrimental consequences in later AD stages. Rather than an alternative etiology, senescence itself may constitute an essential component of the cascade in the amyloid cascade hypothesis.