Keep neuroinflammation in mind when addressing Alzheimer's disease: A microglia perspective

Alzheimer's disease (AD) is the major cause of dementia, characterized by amyloid-β (Aβ) deposits, tau hyperphosphorylation, and neuroinflammation triggered by microglial activation. The immune cells in the brain called microglia, which form clusters surrounding Aβ deposits, are an important pathogenic feature of AD and play a major role its progression.^1,2 Interestingly, a number of AD risk genes are overexpressed in microglia. During AD development and in reaction to Aβ or adjacent neuronal injury, microglia change from a ramified, homeostatic state to an amoeboid, phagocytic state by upregulating many genes such as TREM2, APOE, CST7, CLEC7A, ITGAX, etc.^3,4 This condition has been referred to as disease-associated microglia (DAM), or just “activated microglia”.^2,3,5

Depending on the nature and stage of the disease, activated microglia can either be detrimental or beneficial. Everything is based on the dichotomy between protection and danger induced by microglia. This particular cell has the double side of the same coin. First of all, when the first amyloid fibrils emerge in the early stages of the disease, they presumably act as a barrier to prevent damage. The microglia recognize these fibrils and proceed to phagocytose and eradicate them. ⁶ On the other hand, however, as the disease aggravates and the amyloid plaques continue to be present in the pathological environment, leading to a chronic inflammatory state, the microglia become dangerous. They alter their profile, accelerating the disease's course and exhibiting impaired tau and Aβ phagocytosis as well as releasing pro-inflammatory cytokines that cause neuroinflammation and injury to synapses and neurons.

Indeed, amyloid plays an important role in the pathogenesis of AD, and the formation of amyloid plaques has been well described in literature, beginning with single amyloid molecules that form dimers, then protofibrils, and finally fibrils that accumulate in the plaques.^7,8 Microglia can phagocytize plaques by using antibodies that specifically target Aβ. ⁹ It is yet unknown, nevertheless, how plaque burden and associated damage are connected. Interestingly, molecular modeling investigations have been performed to study the interaction types between amyloid molecules in an attempt to block fibril formation. Furthermore, following the screening of a large number of low molecular weight compounds, it was found that some peptides might alter the process of aggregation and generate new, less hazardous aggregated macrostructures. ¹⁰ The substances in question were named “decoys” by the authors who, interestingly, recently discovered one decoy, NSC16224, that not only inhibits amyloid aggregation but also significantly lowers the amount of proinflammatory cytokines, such as TNFα and IL6, generated by microglia stimulated by Aβ₄₀ and Aβ₄₂. ¹¹

The search for an AD-treatment has been a difficult task that currently has resulted in only a few therapeutics all with relatively limited efficacy. For a long time, the opportunity of employing drugs that might target the amyloid peptide has captured the interest of researchers due to the presence of amyloid deposits. Advantages and limitations have accumulated throughout time. Three monoclonal antibodies (mAbs) against Aβ have been produced and introduced into the clinic: aducanumab, lecanemab, and donamemab.^9,12,13 Unfortunately, several clinical programs have failed, e.g., aducanumab which was withdrawn, while lecanemab and donanemab were recently proven to delay disease-progression in large clinical trials. It has so far not been proven possible to inhibit the production of Aβ aggregates in advance due to the non-specific nature of amyloid-β protein precursor-processing mechanisms, which are shared by many other proteins. Therefore, as another option, Oasa et al. suggest avoiding Aβ aggregation. ¹⁴ Similarly, reducing, if not completely stopping, the production of proinflammatory cytokines from microglia that produce neuroinflammation becomes an appealing approach to combating AD, considering it as an additional effort to block the intricate mechanism that causes disease. Interestingly, enhancing microglial beneficial activity during and after treatment may help boost the efficacy of mAbs.

From pharmacological and pharmaceutical points of view, however, peptides are not excellent drug candidates. ¹⁵ Until recently, it has proven difficult to orally administer larger and more complex peptides, partly because stomach endopeptidases break them down. Furthermore, the large molecular weight of peptides restricts their ability to cross the blood-brain barrier (BBB). The best drug is usually acknowledged to be those in tablet or nasal spray form, which allows the patient to administer themselves, and that, as a self-administering pharmaceutical formulation, is widely acknowledged as the ideal drug. Therefore, more studies will be needed to optimize the pharmacokinetic profile of these decoy peptides and characterize any possible toxicities in order to minimize them.

A further consideration to keep in mind is that A1 astrocytes, which are toxic to neurons, can be triggered by active microglia via the release of pro-inflammatory cytokines. Thus, it would be intriguing to examine how NSC16224 decoy affects different polarized astrocytes.

Reducing the neuroinflammatory response induced by microglia is one strategy to decrease neuroinflammation, such as by blocking TNF-α signaling. Decoy NSC16224, as described by Oasa et al., exhibits potential in suppressing inflammatory responses. ¹¹ Therefore, more pharmacological research is required to examine how decoys affect neuroinflammation and determine how they might influence important brain signaling cascades, such as ApoE- or Aβ-induced TREM2, or other signaling pathways, which would otherwise obscure the effects of the peptide.

In conclusion, further research is necessary to fully comprehend the function of decoys in controlling neuroinflammation in AD. A number of interesting unknowns remain, and we can collect them here as follows:

What happens when findings obtained in microglia are transferred to complex “in vitro” models e.g., co-culturing microglia, astrocytes and neurons, then to “in vivo” animal models for AD and ultimately into clinical trials involving humans?

Is microglia-modulated cytokine release able to influence astrocyte roles through direct or indirect mechanisms?

What are the specific molecular pathways in microglia that are tuned by the decoy?

Does the decoy NSC16224 enter through the BBB?

Which strategies could be used to bypass the BBB-maybe intranasal administration or linking the compound to a transporter?

Prevention and new therapeutics for AD are clearly needed, as seen by the pipeline for 2024 having a similar number of repurposed compounds and fewer new chemical entities as that of 2023, which are tested in a lesser number of total clinical trials. ¹⁶ As neuroinflammation is now considered the third hallmark of AD, alongside hyperphosphorylated tau protein and Aβ accumulation, keeping microglia in mind when addressing AD could make the difference to winning the fight against this severe disease. ¹⁷ Therefore, recognizing the function of microglia in neuroinflammation, understanding microglial dynamics, knowing how they work, and investigating novel opportunities for therapy will all contribute to our potential to combat AD more successfully.