Senescence as an Amyloid Cascade: The Amyloid Senescence Hypothesis

Abstract

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.

Keywords: Alzheimer’s disease; Neurodegeneration; cell cycle; reactive oxygen species; senescence; senescence associated secretory phenotype.

FIGURE 1

Diagram depicting possible ways in which AβO can induce senescence in neurons and or glial cells. AβO can induce unscheduled cell cycle entry in neurons leading to senescence (a). AβO can also induce ROS, either downstream of aberrant activation of post-synaptic receptors (e.g., NMDAr) in neurons (b) or independent of receptor activation in neurons and or glial cells (c). Senescent neurons and or glial cells may develop the SASP. SASP factors released from senescent neurons and or glial cells can result in inflammation and secondary senescence, spreading the disease. Major SASP regulators p38 and NF-kB may also elicit tau hyperphosphorylation, potentially linking the SASP to NFTs in neurons.

FIGURE 2

Proposed model of the amyloid-senescence hypothesis. 1. AβO burden appears 15 to 25 years prior to clinical onset of AD. At this point, antibody-mediated clearance is effective. 2. AβO causes foci of senescent neurons, astrocytes, microglia, OPCs, and or NPCs by inducing aberrant cell cycle entry and or persistent ROS and DNA damage. Senescence cells and the SASP cause oxidative stress, inflammation, and initial stages of cognitive impairment. At early stages, the BBB is healthy. NKs cannot access the brain parenchyma to clear senescent cells, which remain viable. Antibody mediated clearance of AβO is no longer effective because senescence is irreversible. Senolytics can stop disease progression 3. Foci of senescent neurons from across the cortex project into the transentorhinal cortex, where deleterious SASP and secondary senescence builds for years to decades. The SASP is accompanied by tau hyperphosphorylation and NFT. Cognitive impairment is accentuated. If too many senescent neurons are present, senolytics may prove fatal as neurons cannot regenerate. Senostatics, which target the SASP without killing cells, are an alternative. 4. Age-associated disruption of the BBB enables NK cell infiltration and the killing of a large pool of senescent neurons, astrocyte, microglia, OPCs, and or NPCs, increasing inflammation and marking the onset of clinical AD. Immune suppression may be the only viable alternative at this stage. Boosting acetylcholine levels can help suppress the NK cell response. Individuals with senile plaques and NFT with a healthy BBB may remain relatively spared.