Rethinking Alzheimer's origins through the lens of an evolutionarily conserved protein variant
For decades, the search for Alzheimer's disease causes has centered on the amyloid cascade hypothesis—the idea that sticky amyloid plaques are the main drivers of this devastating neurodegenerative condition. Yet, treatments targeting these plaques have shown limited success, suggesting crucial pieces of the puzzle are missing.
PS2V isn't merely a cellular mistake but may be an evolutionarily conserved mechanism that, when dysregulated in the aging brain, contributes to disease.
Enter PS2V, an unusual variant of the Presenilin-2 (PS2) protein that represents a fascinating new frontier in Alzheimer's research. Discoveries reveal that PS2V isn't merely a cellular mistake but may be an evolutionarily conserved mechanism that, when dysregulated in the aging brain, contributes to disease. This article explores the science behind PS2V and how what once may have been a beneficial survival adaptation could potentially turn destructive in later life.
To understand PS2V, we must first meet its parent molecule: Presenilin-2 (PS2). Along with its close relative Presenilin-1 (PS1), PS2 forms the catalytic core of the γ-secretase complex—a cellular machine that chops up other proteins inside our cells 9 .
One of its most famous targets is the amyloid precursor protein (APP). Through a series of cleavages, γ-secretase helps determine whether harmless or potentially problematic amyloid fragments are produced 9 .
Under normal circumstances, the PS2 gene provides instructions for building the standard PS2 protein. However, in a process called alternative splicing, cells can sometimes edit the genetic instructions, creating different versions of the same protein.
PS2V is one such version—an aberrantly spliced form of PS2 that skips exon 5 of its genetic code 5 .
This isn't just a rare occurrence. Research shows that PS2V is a diagnostic feature of sporadic Alzheimer's disease and is significantly elevated in the brains of affected individuals compared to healthy controls 1 5 . What makes this particularly intriguing is that our ancient evolutionary relatives appear to have a similar splicing mechanism, suggesting this isn't merely a biological error but potentially a conserved response with deep evolutionary roots 2 .
The conventional view suggests that PS2V results from faulty cellular machinery. Supporting this:
Compelling evidence suggests a more complex story. Research has revealed that zebrafish possess a PS2V-like isoform, produced from their PSEN1 gene rather than PSEN2 2 .
The molecular mechanism controlling PS2V formation was likely present in the ancient common ancestor of both PSEN1 and PSEN2 genes 2 .
Even more remarkably, despite 400 million years of evolution, human PS2V and the zebrafish PS1V share conserved abilities to stimulate γ-secretase activity and suppress the unfolded protein response (UPR) under hypoxic conditions 2 .
"This suggests that what we're observing isn't merely a defect but a deeply embedded cellular program that has been preserved across evolutionary timescales."
To understand how PS2V arises in sporadic Alzheimer's, researchers designed elegant experiments to identify the molecular players involved. One crucial study sought to determine how hypoxia (low oxygen conditions) triggers PS2V formation and what this might mean for brain cells 5 .
Human neuroblastoma cells (SK-N-SH cells, a model for neurons) were exposed to low-oxygen conditions to mimic aspects of the aged brain environment 5 .
Researchers purified proteins that bound to exon 5 of the PS2 gene, suspecting that a specific factor might be regulating the splicing process 5 .
Through careful analysis, they identified the responsible protein as High Mobility Group A1a (HMGA1a) 5 .
Using advanced microscopy, they observed that under hypoxia, HMGA1a accumulated in nuclear speckles alongside the splicing factor SC35 5 .
The team overexpressed HMGA1a in cells to confirm it could generate PS2V, and then attempted to reverse this effect by introducing other proteins that might interfere with the process 5 .
Finally, they examined brain tissue from sporadic Alzheimer's patients to confirm that HMGA1a levels were significantly increased 5 .
Under hypoxic conditions, HMGA1a expression increases, causing it to bind to a specific sequence on exon 5 of the PS2 gene, interfering with normal splicing.
The findings revealed a novel mechanism: under hypoxic conditions, HMGA1a expression increases, causing it to bind to a specific sequence on exon 5 of the PS2 gene. This binding interferes with the normal splicing machinery, particularly by disrupting U1 snRNP binding to the 5' splice site. The consequence? Exon 5 gets skipped during mRNA processing, and PS2V is born 5 .
| Feature | Normal PS2 | PS2V (Aberrant Form) |
|---|---|---|
| Genetic structure | Contains all exons | Lacks exon 5 due to alternative splicing |
| Inducing conditions | Normal cellular conditions | Hypoxia, sporadic Alzheimer's pathology |
| γ-secretase activity | Standard levels | Increased activity 2 |
| Unfolded Protein Response | Normal regulation | Suppressed under hypoxia 2 |
| Evolutionary conservation | Standard presenilin | Conserved from zebrafish to humans 2 |
| Association with disease | Familial AD mutations | Sporadic, late-onset AD 1 |
Most importantly, this mechanism was confirmed in human brain tissue, establishing a direct link between HMGA1a, PS2V formation, and sporadic Alzheimer's pathology 5 . This provides a plausible explanation for how age-related conditions like reduced cerebral blood flow (creating hypoxic microenvironments) might trigger molecular changes that contribute to Alzheimer's development.
Why would such a mechanism be evolutionarily conserved? The likely answer lies in PS2V's ability to help cells survive stressful conditions:
The very adaptations that might be beneficial temporarily become problematic when chronically activated in the aging brain:
| Experimental Finding | Biological Significance | Research Evidence |
|---|---|---|
| Hypoxia inducibility | PS2V forms when oxygen levels drop | Human neuroblastoma cells under low oxygen 5 |
| HMGA1a involvement | Identified key regulator of splicing | Protein purification and binding studies 5 |
| Conserved function | Similar splicing in zebrafish PSEN1 | Evolutionary analysis across species 2 |
| γ-secretase stimulation | Alters amyloid precursor processing | Activity assays in cell models 2 |
| UPR suppression | Modulates cellular stress response | Hypoxia exposure experiments 2 |
| Research Tool | Primary Function | Application in PS2V Research |
|---|---|---|
| Chromatin Immunoprecipitation (ChIP) | Identifies protein-DNA interactions | Mapping HMGA1a binding to PS2 gene 4 |
| Isoform-sequencing (Iso-Seq) | Characterizes complete transcript isoforms | Detecting PS2V and other splicing variants 1 |
| Hypoxia chambers | Creates low-oxygen cell environments | Inducing PS2V formation in neuronal cells 5 |
| SH-SY5Y cells | Human-derived neuronal model | Studying PS2V effects in neuron-like environment |
| siRNA gene knockdown | Reduces specific gene expression | Testing PS2 function by lowering its expression |
| Aequorin calcium probes | Measures intracellular calcium levels | Detecting calcium homeostasis changes |
Cell lines and animal models enable researchers to study PS2V in controlled environments.
Advanced sequencing and imaging techniques reveal PS2V's molecular mechanisms.
Gene editing and manipulation allow for functional studies of PS2V.
The story of PS2V represents a paradigm shift in how we consider Alzheimer's origins. Rather than viewing it as purely a disease of accumulating proteins, we're beginning to appreciate Alzheimer's as potentially involving the dysregulation of ancient adaptive mechanisms. The PS2V response, which may have evolved to help our ancestors' brains survive temporary oxygen deprivation, becomes maladaptive when persistently activated in the aging brain.
This new perspective opens exciting therapeutic possibilities. Rather than merely targeting amyloid plaques, future treatments might focus on:
As research continues to unravel the complexities of PS2V, we move closer to understanding not just what goes wrong in Alzheimer's disease, but why—at the most fundamental evolutionary level—these processes exist in the first place.
The answers may transform how we approach not only treatment but ultimately prevention of this devastating condition.
"The PS2V response represents an evolutionary trade-off—a short-term survival mechanism with long-term pathological consequences when chronically activated in the aging brain."