From quartz crystals and electrical charges to bone formation, sensory processing and the brain's waste-disposal system.
From high school to the research lab
Key points
• PIEZO1 and PIEZO2 are proteins that let cells sense physical force. Despite the name, they are not piezoelectric crystals: they are mechanically activated ion channels.
• In bone, PIEZO1 helps osteocytes respond to mechanical loading. In aged mice, activating it restored the bone response, but only when combined with loading.
• In mouse models of autism, PIEZO2 has been linked to tactile hypersensitivity and to oxytocin signalling. Evidence in autistic people is still missing.
• In the brain, PIEZO1-related signalling has been linked both to improved fluid transport (ultrasound in Alzheimer's mice) and to synapse loss triggered by bacterial lipopolysaccharide (LPS) in mice. These results look contradictory, and they suggest a "Goldilocks" receptor: not too little, not too much.
• A small human study of a vibrating mattress combined with nitric oxide raised blood levels of brain-derived Alzheimer's proteins. This may indicate increased waste clearance from the brain, which could be very beneficial.
A reason to pay attention in physics class
There is a connection between a principle
taught in high-school physics and some of the more interesting developments in
modern medicine.
The piezoelectric effect describes how certain
materials generate an electrical charge when mechanical pressure is applied.
More than a century later, scientists found that our own cells contain
specialised proteins that detect mechanical forces and convert them into
electrical and biochemical signals. They are called PIEZO channels, from the
Greek piezein, to squeeze or press.
A clarification is needed at the start. PIEZO
channels are not piezoelectric crystals, and they do not generate charge in the
way quartz does. They are proteins in the cell membrane that open when the
membrane is stretched or deformed, letting ions flow in. The name reflects a
shared idea (force in, electrical signal out) rather than a precisely shared
physical mechanism.
Research into these channels is opening up
connections between exercise and bone strength, sensory processing in autism,
oxytocin signalling and the movement of fluid through the brain. Sometimes the
physics lesson you thought you would never use turns out to be relevant to some
of the more interesting questions in medicine.
From piezoelectric crystals to biological sensors
The piezoelectric effect was discovered in
1880 by the French physicists Pierre and Jacques Curie. They showed that
pressure applied to certain crystals, including quartz, could generate an
electrical charge. The reverse effect also occurs: applying an electrical field
can make certain materials change shape.
In 2010, a team in Ardem Patapoutian's
laboratory identified two previously unknown mechanically activated ion
channels, named PIEZO1 and PIEZO2. Patapoutian shared the 2021 Nobel Prize in
Physiology or Medicine with David Julius for discoveries concerning receptors
for temperature and touch.
PIEZO proteins sit within cell membranes. When
a cell is stretched, compressed or otherwise mechanically deformed, these
channels can open, allowing positively charged ions, particularly calcium, to
enter the cell. This converts a physical force into an electrical and
biochemical signal. The process is known as mechanotransduction.
PIEZO1 and PIEZO2 have different distributions
and functions. PIEZO1 is particularly important in blood vessels, lymphatic
vessels and bone. PIEZO2 is especially important in sensory neurons, where it
helps us detect touch, pressure, body position and movement.
The distinction matters because the same
general mechanism can have very different consequences depending on which cells
express the channel, and, as we will see, on the context.
1. PIEZO1 and osteoporosis: why mechanical loading matters
Bone is not an inert structure. It is living
tissue that constantly remodels itself in response to mechanical demands.
One of the most important cells involved is
the osteocyte. These cells are embedded within the bone matrix and act as
sensors, detecting mechanical loading and the movement of fluid through the
tiny channels surrounding them.
When we walk, run, jump or lift weights,
forces are transmitted through bone. Osteocytes detect these forces and
communicate with other bone cells, helping regulate the balance between bone
formation and bone resorption.
PIEZO1 appears to be an important part of this
sensing mechanism. When mechanical forces activate PIEZO1 in osteocytes,
calcium enters the cells and triggers downstream signalling, including pathways
involving Wnt signalling, and other regulators of bone remodelling.
One consequence is the regulation of
sclerostin, a protein that normally inhibits bone formation. Mechanical loading
can reduce sclerostin signalling, allowing bone-building activity to increase.
This helps explain why appropriate mechanical loading is so important for
maintaining bone density.
Does the response to PIEZO1 weaken with age?
A study published in August 2026 examined why
older bone becomes less responsive to mechanical stimulation.
The researchers used 19-month-old mice and
found that their bones had a blunted anabolic response to mechanical loading.
Giving Yoda1, a chemical compound that activates PIEZO1, was also insufficient
on its own. However, combining Yoda1 with mechanical loading restored the
anabolic response in aged cortical bone.
The research findings suggest that age-related changes in how osteocytes
respond to mechanical forces may be partly overcome by enhancing PIEZO1
signalling while providing an appropriate mechanical stimulus.
The distinction matters: the study does not
show that PIEZO1 simply disappears with age. It shows that the bone's response
to mechanical stimulation becomes less effective, and that PIEZO1 activation
can help restore that response.
Yoda1 is a research compound, not an approved
osteoporosis treatment, and the findings are from mice, so we cannot yet assume
the same approach will work in people. The result does offer a molecular
explanation for why mechanical loading matters, and it raises the possibility
that future osteoporosis treatments might combine mechanical stimulation with
drugs that help bone cells sense that stimulation.
2. PIEZO2 and autism: could sensory hypersensitivity involve
mechanical sensing?
Many autistic people have unusual sensory
responses. Touch, pressure, clothing, hair brushing, light contact or
unexpected physical contact can be uncomfortable or even painful.
The mechanisms are complex. They may involve
sensory receptors, peripheral nerves, spinal processing and the way the brain
interprets incoming signals. PIEZO2 is a natural candidate for investigation
because it is one of the principal proteins responsible for detecting
mechanical stimuli.
Human genetic studies have already shown how
important PIEZO2 is. People with rare loss-of-function mutations can have
profound difficulties with proprioception, the sense of where their body is in
space, as well as abnormalities in discriminative touch. This establishes that
PIEZO2 is essential for normal human mechanosensation. It does not establish
that PIEZO2 abnormalities are a general cause of autism.
PIEZO2 and tactile hypersensitivity in an autism mouse model
A 2025 investigated PIEZO2 in BTBR mice, a
commonly used animal model of autism.
The researchers found increased IGF-1
signalling in dorsal root ganglia, clusters of sensory nerve cells outside the
spinal cord. IGF-1 appeared to regulate PIEZO2 expression, and they identified
an IGF-1-PIEZO2 pathway associated with tactile hypersensitivity. Interfering
with this pathway reduced tactile hypersensitivity and also improved some
social behaviours in the mice. A gentle-touch intervention reduced the abnormal
expression of IGF-1 and PIEZO2 in sensory ganglia and improved the measured
behavioural outcomes.
There are three implications. First, sensory
hypersensitivity may not be only a problem of how the brain processes sensory
information; some of the difference may originate further down the sensory
pathway, in the peripheral nervous system. Second, excessive activation or
expression of a mechanosensory pathway could contribute to an exaggerated
response to ordinary physical stimuli. Third, it raises the question of whether
different forms of tactile stimulation could influence sensory signalling.
PIEZO2, oxytocin and social behaviour
A study in July 2025 asked whether mechanical
stimulation could influence oxytocin-producing neurons in the hypothalamus, a
brain region involved in social behaviour, stress responses and hormonal
regulation.
The researchers injected superparamagnetic
iron oxide nanoparticles directly into the paraventricular nucleus of the
hypothalamus in mice. A rotating magnetic field then produced mechanical
stimulation, and the results depended on frequency. At 10 Hz, the system
increased PIEZO2 expression in oxytocin-producing neurons, leading to calcium
influx and increased oxytocin signalling. In mice exposed to valproic acid
during development, an experimental autism model, the intervention improved
several autism-like behavioural measures. When the researchers reduced PIEZO2
expression, the beneficial effects were lost, which suggests PIEZO2 was part of
the mechanism linking mechanical stimulation to oxytocin release.
Is PIEZO1 itself an autism-related gene?
There are also some emerging genetic and
epigenetic observations involving PIEZO1.
A 2026 study analysed de novo genetic variants
in 41,367 parent-child trios from three family-based cohorts. PIEZO1 appeared
among a group of genes showing statistically significant male-specific
enrichment in one of the gene-based analyses. This is potentially relevant
given autism's well-known sex bias. But it is a preprint that has not yet been
peer reviewed, the study included both affected and unaffected individuals, and
the findings do not establish PIEZO1 as a recognised high-confidence autism
gene. It is a candidate for further investigation.
A separate 2025 study examined DNA methylation
of PIEZO1 in infants with neurodevelopmental disorders. The researchers studied
24 infants with neurodevelopmental disorders and 22 typically developing
infants, and found lower methylation at a group of PIEZO1 sites in the clinical
group. Methylation can influence gene regulation, so this raises the
possibility that PIEZO1 expression is altered during early neurodevelopment.
But the clinical group was a mixture of conditions rather than autism alone,
methylation was measured in buccal cells rather than brain tissue, and the
researchers did not measure PIEZO1 gene or protein expression. It is an early
observation, not evidence of a specific autism mechanism.
What does this mean for autism?
We now have several separate lines of
research:
•
PIEZO2 may contribute to tactile
hypersensitivity through sensory neurons outside the brain (mice).
•
PIEZO2 may influence oxytocin release
through hypothalamic neurons (mice).
•
PIEZO1 has appeared in a large genetic
analysis as a candidate requiring further investigation.
•
PIEZO1 methylation differences have
been reported in a small group of infants with neurodevelopmental disorders.
These findings suggest that mechanosensitive ion
channels may be relevant to several biological processes already of interest in
autism research, and different individuals or subgroups could have quite
different alterations.
Where this leaves us. The
most informative next steps would be human studies that measure tactile
detection and discomfort thresholds in autistic participants alongside PIEZO2
genotyping or expression data; peer-reviewed replication of the PIEZO1 de novo
variant signal; and replication of the methylation finding in larger,
autism-specific groups. Until then, PIEZO2 is a plausible mechanism for some
sensory differences, not an established one.
3. PIEZO1, brain pulsations and Alzheimer's disease
The brain has its own system for moving fluid
and clearing waste products, commonly referred to as the glymphatic system. It
involves the movement of cerebrospinal fluid (CSF) along pathways surrounding
blood vessels, with exchange between CSF and fluid in the brain tissue. Waste
products, including soluble amyloid-beta, can then be carried towards drainage
pathways. The system appears to be particularly active during sleep.
The glymphatic concept is
still debated. Some researchers question how much fluid is moved by bulk flow
rather than diffusion, how reliably clearance can be measured in humans, and
whether sleep and anaesthesia change it in the way early mouse studies
suggested.
Why does PIEZO1 matter here? Blood vessels
constantly expand and contract in response to changes in blood pressure and
flow, and these movements create mechanical forces that can influence the
surrounding fluid. PIEZO1 is expressed in vascular endothelial cells, which
line blood vessels, and lets them detect mechanical forces and change their
signalling. This provides a possible link between vascular pulsations,
mechanical stimulation and the movement of fluid through the brain. If these
processes become less effective with age, the clearance of soluble proteins
could be affected, which would be relevant to Alzheimer's disease, where
accumulation of amyloid-beta and other abnormal proteins is a major feature.
Ultrasound activates a PIEZO1-related pathway in Alzheimer's mice
A 2026 study investigated whether
low-intensity focused ultrasound could improve glymphatic-associated transport
in 5xFAD mice, a widely used Alzheimer's disease model. The researchers applied
ultrasound to the hippocampal region over four weeks.
They reported increased CSF tracer movement
into the brain and improved transport of solutes through brain tissue. They
also found increased soluble amyloid-beta in deep cervical lymph nodes, reduced
amyloid deposits in the hippocampus and prefrontal cortex, and improvements in
learning and memory tests. The effects were accompanied by increased PIEZO1
signalling in brain vascular tissue, and when the researchers inhibited
PIEZO1-related signalling, many of the benefits were reduced.
This is experimental evidence that
PIEZO1-related mechanotransduction may contribute to the effects of ultrasound
on brain fluid transport. It remains an animal study and does not show that
ultrasound can prevent or treat Alzheimer's disease in humans.
PIEZO1, gut bacteria and microglia: a double-edged sword?
So far PIEZO1 has appeared as a helpful
sensor: it helps bone respond to loading, and its activation was linked to
better fluid transport in the ultrasound study. A 2025 paper suggests the
picture is less simple.
The researchers were interested in
lipopolysaccharide (LPS), a component of the outer wall of Gram-negative
bacteria and a powerful inflammatory trigger. LPS has been found at higher
levels in Alzheimer's brains, but it is not clear how it gets past the blood-brain
barrier. One suggestion is that it travels inside bacterial extracellular
vesicles (bEVs), tiny membrane packages released by gut bacteria.
The team isolated bEVs from the faeces and
blood of people and mice. LPS levels in these vesicles, or in plasma vesicles
overall, were higher in people with Alzheimer's disease or mild cognitive
impairment than in healthy controls. In mice, vesicles from Gram-negative
bacteria reached the brain, while those from Gram-positive bacteria did not.
Neutralising the LPS, or using bacteria engineered to lack it, prevented the
vesicles from getting in.
Once in the brain, the vesicles activated
microglia, raised levels of the complement proteins C1q and C3, and led to loss
of synapses within 24 hours, with microglia engulfing more synaptic material.
PIEZO1 was involved. The vesicles increased Piezo1 and calcium levels in
microglial cells, and blocking Piezo1 with the inhibitor GsMTx4 reduced the
effect. Mice lacking Piezo1 in myeloid cells (the cell family that includes
microglia) were largely protected from the synapse loss. Samples of Alzheimer's
cortex also showed more Piezo1 in microglia.
This looks very different from earlier work. A
2023 study in cultured microglia found that activating PIEZO1 with Yoda1 reduced
LPS-induced inflammation, and other work suggests PIEZO1 may help microglia
engulf amyloid plaques. The authors of the new paper themselves describe PIEZO1
as a "double-edged sword".
Several cautions apply. Most experiments were
short-term injections of vesicles into young mice, with synapse counts at 24
hours. There were no memory tests and no chronic Alzheimer's model, and several
comparisons used only three animals per group. GsMTx4 is a non-specific
inhibitor and only partly blocked the effects. Here PIEZO1 seems to be switched
on by vesicle uptake and inflammation rather than by physical force, so this is
not mechanotransduction in the usual sense. It is a mouse and cell-culture mechanism,
not a treatment.
It does carry a lesson for the rest of this
post: boosting PIEZO1 in one tissue says little about what it will do in
another. I return to this in Section 6.
Thanks to our reader Stephen for suggesting a
post on LPS and PIEZO1.
4. The vibrating mattress: a new human study
The story took another turn with a study
published in November 2026. Researchers investigated a combination of nitric
oxide-mediated vasodilation and a specially designed whole-body vibration
intervention intended to stimulate PIEZO1. The study involved 29 healthy
adults.
The vibration was delivered with a
commercially available Neurosonic Mobile Mattress, using a specially modulated
vibration pattern rather than simple continuous vibration. The researchers also
gave a sublingual nitric oxide intervention. Nitric oxide causes blood vessels
to relax and dilate, while mechanical stimulation of PIEZO1 can produce
complementary changes in vascular signalling. The idea was to influence the
movement of blood and fluid through the brain by combining the two mechanisms.
Nitric oxide is a recurring theme on this blog, including the vascular effects
of agmatine and eNOS.
Following the combined intervention, the
researchers measured increases in blood levels of several brain-derived
proteins:
• Amyloid-beta 40 (Aβ40)
• Amyloid-beta 42 (Aβ42)
• Glial fibrillary acidic protein (GFAP)
They also observed changes in MRI measurements
of brain fluid dynamics and brain pulsations. A similar rise in blood levels of
brain-derived proteins was reported after intermittent hypercapnia, which I
discussed in July so the mattress result fits a developing pattern in which
vascular oscillations are associated with proteins appearing in the blood.
What the study does and does not show
The increases in circulating proteins are
consistent with a temporary movement of soluble brain-derived proteins towards
the bloodstream. That is a hypothesis, not the only possible reading. Release
from blood cells or the vessel wall, the haemodynamic effects of vasodilation
and a falling blood pressure, or, in the case of GFAP, an astroglial stress
response could all contribute. Telling these apart would need studies that
measure clearance directly, follow the proteins over a longer period and
include control interventions.
The effect was also acute. A rise in blood
proteins after a single session does not show net clearance from the brain over
time. An increase in amyloid-beta in the blood does not prove that amyloid
plaques have been removed, and it does not demonstrate better memory, reduced
Alzheimer's risk or any clinical benefit. The study was small and involved
healthy volunteers, not people with Alzheimer's disease.
It is nonetheless a first human indication
that a PIEZO1-targeted mechanical intervention may influence brain fluid
dynamics and the movement of brain-derived proteins, and a bridge between
laboratory work on PIEZO1 and the possibility of non-pharmacological ways to
influence brain fluid transport.
5. Could glymphatic dysfunction also be relevant to autism?
This brings us back to a question I have
raised before on this blog: could impaired glymphatic drainage be relevant to
autism?
A study in August 2026 adds a piece of
evidence. Researchers analysed MRI data from five cohorts in the Autism Brain
Imaging Data Exchange, involving 250 participants: 128 autistic individuals and
122 neurotypical controls. They used diffusion tensor imaging analysis along
the perivascular space (DTI-ALPS), an indirect MRI measure that estimates water
diffusion along pathways associated with blood vessels. It is sometimes used as
a proxy for glymphatic function, although it does not directly measure clearance
of waste products from the brain.
They found lower ALPS index values in the
autistic group overall. The difference was particularly apparent in adults:
there was no significant group difference among participants younger than 18,
whereas autistic adults had lower values than neurotypical adults. Among
autistic adults, the ALPS index was also associated with depressive symptoms,
but not with IQ or the measured severity of autistic traits.
How this fits with earlier findings
In July I discussed a study of 78 autistic
children and 48 typically developing controls that reported reduced DTI-ALPS
values in children. The August analysis found no significant difference under
18, so the picture in children is not yet consistent. Differences in cohorts,
scanners, age ranges and analysis methods could all contribute, and taken
together the studies suggest a possible difference rather than an established
one.
The interpretation needs care. The August
study was cross-sectional, so it cannot tell us whether reduced perivascular
fluid movement contributes to autism, develops later in life, or reflects other
factors. Sleep, vascular function, mood and other health factors could all be
relevant, and DTI-ALPS is an indirect marker rather than a direct measurement
of glymphatic clearance.
If future studies confirm that some autistic
people have altered glymphatic function, it would be worth asking whether this
is associated with sleep disturbances, vascular differences or other biological
features, and whether interventions that influence vascular pulsations or
mechanical signalling have any relevance. At present, there is no evidence that
vibrating mattresses or other PIEZO-targeted interventions improve glymphatic
clearance in autistic people.
6. One principle, many applications: a Goldilocks receptor
What makes PIEZO research so interesting is
that one biological mechanism lets physical forces influence very different
systems. In bone, mechanical loading helps osteocytes regulate bone formation.
In the peripheral nervous system, PIEZO2 helps detect touch, pressure and body
position. In the hypothalamus, PIEZO2 can influence oxytocin-producing neurons.
In blood vessels and lymphatic vessels, PIEZO1 helps cells respond to
mechanical forces. And in the brain, these processes may influence the movement
of fluid and the clearance of soluble proteins.
It is tempting to think of PIEZO channels as a
universal switch that could be turned up to improve health. The evidence points
the other way. PIEZO looks more like a Goldilocks receptor: not too little, not
too much.
•
Bone:
Yoda1 alone did not restore the response in aged mouse bone. It worked when
combined with mechanical loading, so the stimulus and the channel both
mattered.
•
Microglia: In
cultured microglia, activating PIEZO1 with Yoda1 reduced LPS-induced
inflammation. In mice, LPS-carrying bacterial vesicles activated microglial
Piezo1 and drove synapse loss. Same channel, opposite-looking outcomes.
•
Stimulus: In
the oxytocin study the effect depended on frequency, and only 10 Hz produced
the described benefit.
The effects depend on which PIEZO channel is
involved, which cells express it, the intensity, timing and frequency of
stimulation, and the biological context. Too little activity may be a problem
in one tissue, while excessive or prolonged activation could be harmful in
another. I would treat "Goldilocks" as a working hypothesis rather
than a finding: the studies show opposite effects in different settings, but
none has mapped a dose-response curve for PIEZO activity.
The research also shows why mechanical
stimulation is attracting renewed interest. Exercise, vibration, ultrasound and
other physical inputs may have biological effects beyond moving muscles or
loading bones, because they can influence how cells sense and respond to their
physical environment. Regular exercise remains the simplest and best-supported
way to apply mechanical stimulus to bone, and I have discussed how exercise may
relate to glymphatic function [link: 22 July 2026 post].
Conclusion
The discovery of PIEZO channels created an
unexpected bridge between physics and biology. A principle first demonstrated
in crystals more than 140 years ago has a biological counterpart in proteins
that let cells convert mechanical forces into electrical and chemical signals.
For osteoporosis, PIEZO1 helps explain how
bones detect mechanical loading and why that response can become less effective
with age. For autism, PIEZO2 research offers possible mechanisms for tactile
hypersensitivity and oxytocin signalling, PIEZO1 deserves further
investigation, and the MRI findings raise the question of whether altered brain
fluid transport matters for some people. For Alzheimer's disease, animal
studies and a small human study suggest that mechanical stimulation of vascular
PIEZO1 pathways may influence brain fluid dynamics, while the LPS work is a
reminder that the same channel can contribute to harm in another context.
Perhaps there really was a good reason to pay attention in physics class.
Selected research papers
PIEZO channels and mechanotransduction
•
Coste B. et al. (2010). Piezo1 and
Piezo2 are essential components of distinct mechanically activated cation
channels. Science. DOI:
10.1126/science.1193270
•
Chesler A.T. et al. (2016). The
Role of PIEZO2 in Human Mechanosensation. New England Journal of Medicine. DOI: 10.1056/NEJMoa1602812
Bone and osteoporosis
•
Zhao D. et al. (2026). Piezo1
Activation Rescues Anabolic Response to Mechanical Loading in Aged Bone via
Connexin 43 Hemichannels. Aging Cell. DOI: 10.1111/acel.70687
Autism and sensory processing
•
Zhai J. et al. (2025). The effect
of modulation Piezo2 by IGF-1 on tactile hypersensitivity in BTBR model mice.
Life Sciences. DOI:
10.1016/j.lfs.2025.123449
•
Liu S. et al. (2025). PIEZO2 is the
underlying mediator for precise magnetic stimulation of PVN to improve
autism-like behavior in mice. Journal of Nanobiotechnology. DOI:
10.1186/s12951-025-03557-x
•
Turner T.N. (2026). De Novo
Variation in Autism by Sex and Diagnostic Status in 41,367 Parent-Child Trios.
medRxiv preprint. DOI:
10.64898/2026.01.26.26344889
•
Mascheroni E. et al. (2025). Exploring
PIEZO1 DNA methylation in infants with neurodevelopmental disorders.
Frontiers in Psychology. DOI:
10.3389/fpsyg.2025.1593609
Alzheimer's disease, microglia and glymphatic
transport
•
Zhang L. et al. (2026). Ultrasound
enhances glymphatic-associated solute transport via Piezo1-related
mechanotransduction in 5xFAD mice. Journal of Cerebral Blood Flow &
Metabolism. DOI:
10.1177/0271678X261470064
•
Tuunanen J. et al. (2026). Vasomechanic
treatment is associated with increased efflux of human brain proteins.
Nature Communications. DOI:
10.1038/s41467-026-78894-y
•
Zhao X., Yu J. et al. (2025). Gut-derived
bacterial vesicles carrying lipopolysaccharide promote microglia-mediated
synaptic pruning. Alzheimer's & Dementia. DOI: 10.1002/alz.70331
•
Piezo1 channel-mediated Ca2+
signalling inhibits LPS-induced activation of the NF-kB inflammatory signalling
pathway and generation of TNF-alpha and IL-6 in microglial cells. Glia
(2023), 71(4):848-865. [author list to be added]
•
The mechanosensitive Piezo1 channel
mechanism of Alzheimer's disease and implications for the development of
therapeutic or early detection strategies.
Frontiers in Aging Neuroscience (2025). DOI:
10.3389/fnagi.2025.1707659 [author list to be added]
Glymphatic function in autism