"Amyloid-beta accumulation cycle" as a prevention and/or therapy target for Alzheimer's disease

Abstract

The cell cycle and its regulators are validated targets for cancer drugs. Reagents that target cells in a specific cell cycle phase (e.g., antimitotics or DNA synthesis inhibitors/replication stress inducers) have demonstrated success as broad-spectrum anticancer drugs. Cyclin-dependent kinases (CDKs) are drivers of cell cycle transitions. A CDK inhibitor, flavopiridol/alvocidib, is an FDA-approved drug for acute myeloid leukemia. Alzheimer's disease (AD) is another serious issue in contemporary medicine. The cause of AD remains elusive, although a critical role of latent amyloid-beta accumulation has emerged. Existing AD drug research and development targets include amyloid, amyloid metabolism/catabolism, tau, inflammation, cholesterol, the cholinergic system, and other neurotransmitters. However, none have been validated as therapeutically effective targets. Recent reports from AD-omics and preclinical animal models provided data supporting the long-standing notion that cell cycle progression and/or mitosis may be a valid target for AD prevention and/or therapy. This review will summarize the recent developments in AD research: (a) Mitotic re-entry, leading to the "amyloid-beta accumulation cycle," may be a prerequisite for amyloid-beta accumulation and AD pathology development; (b) AD-associated pathogens can cause cell cycle errors; (c) thirteen among 37 human AD genetic risk genes may be functionally involved in the cell cycle and/or mitosis; and (d) preclinical AD mouse models treated with CDK inhibitor showed improvements in cognitive/behavioral symptoms. If the "amyloid-beta accumulation cycle is an AD drug target" concept is proven, repurposing of cancer drugs may emerge as a new, fast-track approach for AD management in the clinic setting.

Keywords: Alzheimer's disease (AD); Shugoshin 1 (Sgo1); amyloid-beta (Aβ); brain; cell cycle; chromosome instability (CIN); cohesinopathy; cyclin-dependent kinase (CDK) inhibitor; mitosis; mouse.

Figure 1

“Complex Pathology of AD”. In the clinic, AD is usually diagnosed with cognitive–behavioral symptoms and verified with brain pathology (i.e., brain scan for amyloid‐beta or observed brain shrinkage). Underlying presymptomatic latent pathologies precede the clinical symptoms by decades. Late‐stage AD patients' brains indicate amyloid‐beta plaques, p‐tau tangles, neurodegeneration, neuroinflammation, and brain shrinkage as widespread pathological traits. Understanding cellular/organ mechanisms driving the development of these pathologies (latent processes) is critical to developing drugs for AD intervention and/or therapy. Amyloid‐beta accumulation is considered a key trigger for AD pathology: (a) pathological amyloid‐beta accumulation precedes p‐tau tangles by 10–15 years (Perrin et al., 2009); (b) oligomeric amyloid‐beta is neurotoxic and can impair neuronal functions (Cline et al., 2018); and (c) amyloid‐beta catabolism is influenced by aging, stress, sleep, and glial cell functions, which is consistent with the fact that 96% of AD is late‐onset/age‐associated (see Text). Amyloid‐beta accumulation is considered a result of balance between amyloid‐beta generation (increased by stress, neuronal activity) and catabolism (which is reduced over age, helped by sleep). The mechanistic question of how amyloid‐beta begins to accumulate in middle age is a critical question

Figure 2

(a) The “amyloid‐beta accumulation cycle”. Normal neurons or glia are challenged by mitotic signaling, which may be associated with age and the microenvironment, such as high reactive oxygen species (ROS), reduced antioxidants, damaged blood–brain barrier, and fatigued stem cells, or other pathogenic conditions, such as diabetic wounds, pathogen infection, or mutated AD risk gene. Mitogenic signaling causes neurons or glial cells to enter the cell cycle and attempt to go through mitosis. In the cycling cells, aneuploidy, an environmental factor, other mutations in an AD risk gene, or already existing extracellular amyloid‐beta cause cells to go through prolonged mitosis or a quasi‐mitotic state with high mitotic kinase activity, when they accumulate amyloid‐beta, BACE, and p‐tau. If the state is not resolved, mitotic catastrophe occurs, and accumulated amyloid‐beta, BACE, and p‐tau are released to the microenvironment. Released amyloid‐beta, with its prion‐like properties, may function as seeds for subsequent plaque pathology. Extracellular amyloid‐beta can provoke inflammation and mitogenic signaling, and can also cause mitotic errors, prolonged mitosis, and aneuploidy. Thus, age‐ or microenvironment‐provoked mitogenic signaling can trigger a vicious cycle leading to further amyloid‐beta accumulation (the “amyloid‐beta accumulation cycle”) (blue/purple arrows). (b) Cancer drugs that target mitotic re‐entry and/or prolonged mitosis may be valid drugs for managing the “amyloid‐beta accumulation cycle” and AD. The two‐hit hypothesis (Zhu et al., 2007, 2004) proposed age and mitotic re‐entry as crucial events for development of AD pathology. In light of the apparent importance of prolonged mitosis in this process, we proposed the three‐hit hypothesis (Rao, Farooqui, Asch et al., 2018). The “amyloid‐beta accumulation cycle” is an integrated hypothesis that emerged from the three‐hit hypothesis. The “amyloid‐beta accumulation cycle” suggests that a reagent that interferes with amyloid‐beta accumulation could be an AD drug. As the cell cycle and mitosis are validated targets for cancer drugs, repurposing of cancer drugs for AD management may emerge as a viable clinical option in the near future. (c) Cerebral amyloid‐beta protein can accumulate in mice with an unmodified APP gene under certain conditions. Under normal circumstances, wild‐type mice with an unmodified APP gene do not accumulate amyloid‐beta in the brain, even in old age (24 months and older). AD modeling in mice has been dependent on introduction of transgenic mutations in genes involved in familial/early‐onset AD (e.g., APP, PSEN1, and MAPT), representing early‐onset AD models (Jankowsky & Zheng, 2017; Saito & Saido, 2018). A rodent model for sporadic late‐onset AD has been an unmet need. Over 96% of all human AD cases are late‐onset and sporadic, a majority of which carry no mutation in known early‐onset AD genes. Thus, identifying conditions under which amyloid‐beta accumulates is valuable to gain mechanistic insights on AD development and to model late‐onset AD. A progeria mouse model SAMP8 was reported to accumulate amyloid‐beta, yet the causal mutation remains unidentified (Akiguchi et al., 2017). Recent reports began to identify conditions that can cause amyloid‐beta accumulation in the mouse brain with unmodified APP or other known early‐onset AD gene mutations. Examples of amyloid‐beta accumulating conditions include (i) aged Sgo1^−/+ mice, a cohesinopathy–chromosome instability mouse model (Rao, Farooqui, Zhang et al., 2018) (photo: Our Aβ IHC results from 18‐ to 24‐month‐old Sgo1^−/+ mice. The magnified panel indicates extracellular “released” Aβ), and (ii) HSV1 infection (e.g., De Chiara et al., 2019). Photo: Our Aβ IHC results from HSV1‐infected 12‐month‐old C57BL/6 mice (unpublished). Uninfected mice showed no cerebral amyloid‐beta (not shown). Antibody used for IHC: Cell Signaling Technology β‐Amyloid D54D2 (cat. No. 8243). Although multiple Aβ‐specific commercial antibodies recognized the same band, the exact Aβ species accumulated in Sgo1^−/+ model remain to be determined