Thread by @ZdenekVrozina

Can pathological processes continue in the brain without an active virus?
Yes.
The SARS-CoV-2 nucleocapsid (N) protein on its own can accelerate microglial aging by switching cellular metabolism toward glycolysis, leading to measurable memory impairment🧵

This study shows that the N protein is not biologically neutral.
Even in the absence of viral replication, it is sufficient to trigger long-lasting dysfunction in the brain.

What exactly is being damaged?
The primary target is microglia, the brain’s immune cells.
They are not merely activated.
They are metabolically reprogrammed.

Mitochondrial energy production is disrupted, cells are forced to rely on glycolysis, and microglia enter a senescent state.
Senescent microglia lose their protective role and instead worsen the neuronal environment, contributing to cognitive decline.

Why does the metabolic switch to glycolysis matter?
The shift toward glycolysis is not a secondary phenomenon.
It is the central mechanism driving pathology.

When glycolysis was inhibited, or when pathological mitochondrial fragmentation was prevented, microglial senescence was reduced and cognitive performance improved in animal models!
This supports a causal relationship, not a coincidental association.

This is a mouse and cell-based study.
It does not claim that the same mechanism operates identically in all humans.

However, the pathway described is biologically coherent and consistent with clinical observations in COVID/long COVID.

This does not mean that COVID inevitably causes neurodegeneration.
It means that SARS-CoV-2 has the biological capacity to push the brain into an aging-like state earlier than expected - even after the virus itself is no longer present.

Yang et al., The SARS-CoV-2 nucleocapsid protein induces microglia senescence-mediated cognitive impairment via glycolysis, Molecular Medicine 2025. link.springer.com/article/10.118…

In HIV, neurological damage can persist even when viral replication is effectively suppressed.
Viral proteins such as Tat, gp120, and to a lesser extent Nef, continue to drive microglial activation, metabolic stress, and synaptic dysfunction, leading to persistent cognitive impairment (HAND).

The principle is the same. Ongoing brain pathology does not require active infection, but can be maintained by viral proteins alone.

Is there a parallel with Alzheimer’s disease? In early Alzheimer’s disease, microglia also shift toward glycolysis, lose their supportive function, and accelerate synaptic decline.

The initiating trigger differs, but the mode of microglial failure is similar.

Why is this particularly important for children?
The developing brain is especially dependent on properly functioning microglia.

If microglia are pushed into a senescent state early in life, the consequences may not be immediately apparent, but can emerge later as difficulties with learning, attention, and cognitive resilience.

This is not about delayed recovery.
It is about altered developmental trajectories.

The hippocampus is a particularly vulnerable target of microglial senescence induced by the N protein.
In this model, the N protein primarily affects microglia in the hippocampus, which secondarily disrupts memory circuits and leads to measurable cognitive impairment.

The child’s hippocampus is still maturing,
and plays a central role in school learning and memory consolidation.
Damage to microglia in this region may not result in acute failure, but can lead to a lasting reduction in cognitive reserve.
The impact may become apparent only later.

@szupraha @ZdravkoOnline @adamvojtech86 @RobertPlaga @msmtcr