Senescent brain cell types in Alzheimer's disease: Pathological mechanisms and therapeutic opportunities

Abstract

Cellular senescence is a cell state triggered by programmed physiological processes or cellular stress responses. Stress-induced senescent cells often acquire pathogenic traits, including a toxic secretome and resistance to apoptosis. When pathogenic senescent cells form faster than they are cleared by the immune system, they accumulate in tissues throughout the body and contribute to age-related diseases, including neurodegeneration. This review highlights evidence of pathogenic senescent cells in the brain and their role in Alzheimer's disease (AD), the leading cause of dementia in older adults. We also discuss the progress and challenges of senotherapies, pharmacological strategies to clear senescent cells or mitigate their toxic effects, which hold promise as interventions for AD and related dementias (ADRD).

Keywords: Alzheimer's disease; Biology of aging; Neurescence; Neurodegeneration; tau.

Fig. 1

Alzheimer's disease pathogenic proteins contribute to brain cell senescence. (a) Overview of the interaction between senescent brain cells with amyloid plaques and pathogenic tau. (b–e) Detailed view of each respective cell type and senescence-associated features reported in the literature: (b) neuron, (c) microglia, (d) oligodendrocyte/oligodendrocyte precursor cell, (e) astrocyte, and (f) blood-brain barrier (BBB) featuring endothelial cells, pericytes, and astrocytes, demonstrating compromised BBB integrity in AD. Mitochondrial dysfunction has been reported in all cell types and is not included for simplicity. Abbreviations: SASP: senescence-associated secretory phenotype; CDKs: cyclin-dependent kinases; CDKIs: cyclin-dependent kinase inhibitors; SA β-gal: senescence-associated beta-galactosidase; TREM2: triggering receptor expressed on myeloid cells 2. Figure created with Biorender.com.

Fig. 2

Mechanisms and applications of senotherapeutics targeting senescence in the brain. (a) Simplified schematic representation of a cell maintaining its senescent state through engaging senescent cell anti-apoptotic pathways (SCAPs). Senolytics such as dasatinib, navitoclax, quercetin, and fisetin inhibit SCAP pathway signaling, thereby promoting senolysis. Senomorphics inhibits the senescence-associated secretory phenotype (SASP). (b) Overview of senolytics currently in clinical trials and senescent cell types they may target as evidenced from laboratory studies. Abbreviations: D+Q: dasatinib plus quercetin; RTK: receptor tyrosine kinase; SASP: senescence-associated secretory phenotype; HSPs: heat shock proteins; OPC: oligodendrocyte precursor cell. Figure created withBiorender.com.