Leukocytes and Endothelial Cells Participate in the Pathogenesis of Alzheimer’s Disease: Identifying New Biomarkers Mirroring Metabolic Alterations

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and changes in behavior. While the primary pathological hallmark is the accumulation of amyloid-β plaques and tau tangles in the brain, emerging research highlights the involvement of various molecular mechanisms, including the role of endothelial cells and leukocytes [1].

Endothelial cells forming the blood-brain barrier (BBB) are essential in maintaining brain homeostasis [2, 3]. In AD, the integrity of the BBB is compromised, allowing the infiltration of peripheral immune cells, including leukocytes, which are known to play a pivotal role in the neuroinflammatory response in AD. Peripheral immune cells, including monocytes and T cells, infiltrate the brain in response to BBB breakdown. While their role in AD is complex, these immune cells contribute to the inflammatory milieu and exacerbates disease progression [4]. The aggregation of amyloid-β peptides, derived from the cleavage of the amyloid-β protein precursor, leads to the formation of neurotoxic plaques. This accumulation disrupts synaptic function and triggers neuroinflammation. Tau protein abnormalities result in the formation of intracellular tangles, disrupting neuronal transport and contributing to synaptic dysfunction. Tau pathology correlates with cognitive decline in AD patients. Activated microglia attempt to clear amyloid-β deposits but can exacerbate inflammation, leading to neuronal damage.

Vascular risk factors, such as hypertension and diabetes, contribute to endothelial dysfunction and increase the risk of AD; chronic inflammation associated with vascular conditions further amplifies the neuroinflammatory response [5]. On these grounds, in this issue of the Journal of Alzheimer’s Disease, Okinaka and collaborators [6] examined the mRNA expression levels of specific genes in circulating mononuclear cells and leukocytes of 10 male patients with AD (Age: 81.3±6.8, Mini-Mental State Examination (MMSE) 16.5±5.3) compared to 10 control subjects (Age: 74.9±11.3, MMSE 29.7±0.35), in the hippocampus of 80-week-old mice compared to 5-week-old mice, and in human umbilical vascular endothelial cells at passage 10 versus passage 3. Intriguingly, the authors observed in all these models a consistent decrease in Cx37/PHD3, i.e., the ratio between Connexin-37 (Cx37, also known as GJA4: Gap Junction Protein Alpha 4) and Prolyl Hydroxylase Domain-Containing Protein 3 (PHD3, also known as EGLN3: Egl-9 Family Hypoxia Inducible Factor 3).

Cx37 is predominantly found in vascular endothelial cells, playing a crucial role in the communication between cells: indeed, gap junctions formed by Cx37 facilitate the direct exchange of signaling molecules and ions [7]. PHD3 is an enzyme that plays a crucial role in cellular responses to hypoxia, functioning as an oxygen sensor, regulating the stability of the hypoxia-inducible factor 1α (HIF1α). Under normoxic conditions, PHD3 hydroxylates specific proline residues on HIF1α, marking it for degradation. However, in hypoxic environments, PHD3 activity decreases, leading to HIF1α stabilization and activation of genes that facilitate adaptation to low oxygen levels [8]. The intricate regulation of PHD3 underscores its significance in cellular oxygen sensing and response mechanisms. These findings are consistent with previous preclinical observations from the same group of investigators [9] showing that the transcription of metabolism related genes in circulating leukocytes are significantly regulated during aging, at least in murine models.

This discovery may have a tremendous impact in the field of AD, and the Cx37/PHD3 ratio could soon represent a novel reliable biomarker for patients with AD. However, this assumption looks quite preliminary at this stage, and a more definitive demonstration should come from dedicated prospective studies. The authors also make some speculations on the potential mechanisms underlying the reduced Cx37/PHD3 ratio in all their models. For instance, the conveyance of glycolytic substrate from leukocytes to endothelial cells through gap junctions could decrease oxygen consumption, subsequently leading to the deactivation of HIF1α-mediated pathways. Henceforth, the transfer of AMP from leukocytes to endothelial cells will result in the inactivation of AMP-activated protein kinase (AMPKα) in leukocytes [10]. Future studies exploring these putative mechanisms are warranted. Equally important, an increased production of reactive oxygen species and decreased antioxidant defenses is known to contribute to neuronal damage; hence the contribution of oxidative stress in the interplay of endothelial cells and leukocytes deserves to be examined. In fact, oxidative stress is interconnected with inflammation, creating a vicious cycle in AD pathogenesis.

In conclusion, understanding the intricate molecular mechanisms involving leukocytes, endothelial cells, and neuroinflammation provides potential therapeutic targets. Strategies aimed at modulating immune responses, restoring BBB integrity, and targeting specific molecular pathways hold promise for AD treatment.