Alzheimer DiseasezTARGETADNCT06677632
Targeting zDHHC Enzymes to Counteract Alzheimer's Disease
An observational study of Alzheimer Disease, run by Fondazione Policlinico Universitario Agostino Gemelli IRCCS at 1 site in Italy.
Trial summary
Alzheimer's disease (AD) is a growing problem for aging populations worldwide and represents one of the most demanding challenges for biomedical and pharmacological research. All therapeutic attempts made so far based on current knowledge have proven scarcely effective, probably because the molecular mechanisms… Read more about this study
- Who is it for?
- Ages 18 to 80 yearsHealthy volunteers can take part
- Conditions the study is for
- Alzheimer Disease
- What is being tested?
- Palmitoylation Enzyme Expression Profiling Study
- How many people
- 14 participants
- Where
- 1 siteItaly
- Study dates
- 11 Nov 2024to 31 Aug 2026
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: The study population will be drawn from adults receiving care at Clinica della Memoria at Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome, Italy
Who may be able to join
- Clinical diagnosis of Alzheimer's Disease
- Age between 18 and 80 years
- Signed informed consent obtained
Who cannot join
- Patients suffering from other neurological diseases;
- Patients with coagulation disorders or in treatment with anticoagulant drugs;
- Patients suffering from dermatological diseases and connective tissue diseases;
- Patients suffering from other organic, psychiatric diseases or laboratory abnormalities could preclude participation or invalidate the study results;
- Inability to give informed consent.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Developing New Therapeutic Strategies to Counteract Synaptic and Cognitive Deficits in Alzheimer's Disease by Targeting zDHHC Enzymes
Alzheimer's disease (AD) is a growing problem for aging populations worldwide and represents one of the most demanding challenges for biomedical and pharmacological research. All therapeutic attempts made so far based on current knowledge have proven scarcely effective, probably because the molecular mechanisms underlying the onset and progression of the disease remain poorly understood. Neuroinflammation and alteration of brain insulin signaling have been demonstrated to induce an AD-like phenotype and accelerate neurodegeneration in the hippocampus and neocortex of experimental models of AD. An increasing number of studies have shown the role of palmitoylated proteins in the regulation of synaptic plasticity and neuronal functions. Aberrant protein S-palmitoylation plays a pivotal role in brain insulin resistance (BIR)-dependent cognitive decline. Moreover, protein S-palmitoylation can target immune signaling pathways (e.g., STING, NOD1/2, JAK-STAT, T cell receptor signaling) and modulate inflammatory responses. Accordingly, S-palmitoylation has been shown to regulate localization and activity of several enzymes involved in cytokine receptor-mediated signaling and neuroinflammation.
Unpublished results showed aberrant protein S-palmitoylation in hippocampal tissues of both AD post-mortem brains and mouse experimental models of AD. Preliminary data reveal a key role of palmitoyltransferase enzymes (zDHHCs), which catalyze the S-palmitoylation of substrate proteins, in the development of neurodegeneration and cognitive deficits, suggesting that counteracting aberrant protein S-palmitoylation can be a novel therapeutic strategy for AD. Nevertheless, to date, therapeutic approaches targeting protein S-palmitoylation have not yet been attempted in AD and there are currently no available drugs specifically targeting zDHHCs.
The goal of this study is to develop novel therapeutic strategies targeting zDHHC enzymes to counteract S-palmitoylation-dependent synaptic and cognitive deficits in AD. Additionally, new biotechnological approaches aimed at inhibiting zDHHCs and their targets will be set up to expand the range of tools capable of interfering with altered protein S-palmitoylation in AD. To this end, a combination of different in vitro and in vivo techniques (electrophysiology, molecular biology, behavioral tests, microscopy studies) will be used in both animal and human models of AD, concurrent with innovative biotechnological strategies.
Read the detailed description
S-palmitoylation is a protein post-translational modification involving the attachment of a palmitic acid molecule to cysteine residues. This modification influences protein trafficking toward cellular membranes and is finely regulated by a class of enzymes named zinc finger DHHC domain containing (zDHHC) S-acyltransferases. Proteins critically involved in Alzheimer's disease (AD), such as APP and BACE1, are targets of S-palmitoylation. Higher levels of S-palmitoylated proteins have been found in both post-mortem brain samples and brain organoids derived from induced pluripotent stem cells (hiPSCs) obtained from AD patients. Notably, both neurons and brain organoids derived from human AD hiPSCs exhibited molecular, morphological, and functional alterations reminiscent of AD. Intranasal administration of the palmitoylation inhibitor 2-bromopalmitate (2-BP) significantly counteracted LTP and memory deficits in 3×Tg-AD mice, extended lifespan, and decreased Aß deposition. Higher levels of zDHHC7 and zDHHC21 were also found in the hippocampus of 3×Tg-AD mice. Silencing of zDHHC7 in the hippocampus of 3×Tg-AD mice prevented cognitive deficits and Aß accumulation, along with counteracting palmitoylation of proteins critically involved in neuronal function. This confirms that modulation of zDHHC activity may be exploited for AD treatment.
The idea underlying this project is based on the assumption that zDHHC enzymes and alteration of protein S-palmitoylation play a key role in the onset and progression of AD. Dysregulated zDHHC activity and aberrant S-palmitoylation of neuronal proteins critically involved in the regulation of brain plasticity, neuroinflammation, and Aß metabolism can affect synaptic function, protein homeostasis, and mitochondrial activity, leading to the development of neurodegeneration and cognitive deficits. A druggable target, zDHHC7, has been identified to test the efficacy of novel therapeutic approaches. This study aims to validate a new strategy targeting zDHHC enzymes in human experimental models of AD. Human models will allow an understanding of the translation potential of these approaches to human disease, to be validated in subsequent clinical trials whose implementation exceeds the duration of the present project.
- Conditions
- Alzheimer Disease
- Being tested
- Palmitoylation Enzyme Expression Profiling Study
- Medical subject headings
- Alzheimer Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Palmitoylation Enzyme Expression Profiling StudyOther
The expression of 23 zDHHC enzymes will be studied in human post-mortem hippocampi of AD patients and controls that have already been collected from UK brain biobanks. zDHHC enzymes will be analyzed at both mRNA and protein levels by Real Time PCR and Western blotting techniques, respectively
| Study group | Role | What they receive |
|---|---|---|
| Alzheimer's disease patients | TO DETERMINE THE EXPRESSION OF zDHHC ENZYMES AND CHANGES OF PROTEIN S- PALMITOYLATION IN THE hiPSC-DERIVED NEURONS AND BRAIN ORGANOIDS OBTAINED FROM AD PATIENTS Receives: Other: Palmitoylation Enzyme Expression Profiling Study |
What is being measured
The primary outcome is the main question the study is designed to answer.
Differences in zDHHC mRNA and protein expression levels between Alzheimer's disease (AD) models and control samples
Levels of zDHHC enzymes will be quantified in AD models and controls to measure potential differences. Real-Time PCR will be used to assess mRNA expression, while Western blotting will measure protein levels, providing detailed profiles of zDHHC expression.
Measured: Year 1
Change in AD-associated deficits following zDHHC7 downregulation
Measurable changes in AD-associated deficits will be assessed after zDHHC7 downregulation, with a focus on alterations in cellular or molecular markers relevant to Alzheimer's pathology.
Measured: Year 1
Secondary outcomes (1)
Decrease in zDHHC enzyme expression in human experimental models of Alzheimer's disease
Levels of zDHHC enzyme expression will be measured to assess the impact of biotechnological interventions aimed at reducing zDHHC activity, with the goal of improving synaptic function in Alzheimer's disease models.
Measured: Year 2
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Nov 2024
- Study start11 Nov 2024 (estimated)
- Primary completion31 Aug 2025 (estimated)
- Study completion31 Aug 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Alzheimer DiseaseStudies of the same condition, open and under way.
- More trials run by Fondazione Policlinico Universitario Agostino Gemelli IRCCSThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 14 participants (estimated)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Claudio Grassi, Principal investigator, Fondazione Policlinico Universitario Agostino Gemelli IRCCS
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06677632
- Sponsor's protocol ID
- 6858
- Acronym
- zTARGETAD
- Status last verified
- Jul 2024
- First submitted
- 31 Jul 2024
- Last updated
- 7 Nov 2024
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 7 Nov 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Developing New Therapeutic Strategies to Counteract Synaptic and Cognitive Deficits in Alzheimer's Disease by Targeting zDHHC Enzymes
- ClinicalTrials.gov ID
- NCT06677632
- Acronym / sponsor ID
- zTARGETAD / 6858
- Conditions
- Alzheimer Disease
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 14 participants (estimated)
- Lead sponsor
- Fondazione Policlinico Universitario Agostino Gemelli IRCCSUniversity, hospital or other
- Study start
- 11 Nov 2024 (estimated)
- Primary completion
- 31 Aug 2025 (estimated)
- Study completion
- 31 Aug 2026 (estimated)
- First posted
- 7 Nov 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Alzheimer's disease (AD) is a growing problem for aging populations worldwide and represents one of the most demanding challenges for biomedical and pharmacological research. All therapeutic attempts made so far based on current knowledge have proven scarcely effective, probably because the molecular mechanisms underlying the onset and progression of the disease remain poorly understood. Neuroinflammation and alteration of brain insulin signaling have been demonstrated to induce an AD-like phenotype and accelerate neurodegeneration in the hippocampus and neocortex of experimental models of AD. An increasing number of studies have shown the role of palmitoylated proteins in the regulation of synaptic plasticity and neuronal functions. Aberrant protein S-palmitoylation plays a pivotal role in brain insulin resistance (BIR)-dependent cognitive decline. Moreover, protein S-palmitoylation can target immune signaling pathways (e.g., STING, NOD1/2, JAK-STAT, T cell receptor signaling) and modulate inflammatory responses. Accordingly, S-palmitoylation has been shown to regulate localization and activity of several enzymes involved in cytokine receptor-mediated signaling and neuroinflammation.
Unpublished results showed aberrant protein S-palmitoylation in hippocampal tissues of both AD post-mortem brains and mouse experimental models of AD. Preliminary data reveal a key role of palmitoyltransferase enzymes (zDHHCs), which catalyze the S-palmitoylation of substrate proteins, in the development of neurodegeneration and cognitive deficits, suggesting that counteracting aberrant protein S-palmitoylation can be a novel therapeutic strategy for AD. Nevertheless, to date, therapeutic approaches targeting protein S-palmitoylation have not yet been attempted in AD and there are currently no available drugs specifically targeting zDHHCs.
The goal of this study is to develop novel therapeutic strategies targeting zDHHC enzymes to counteract S-palmitoylation-dependent synaptic and cognitive deficits in AD. Additionally, new biotechnological approaches aimed at inhibiting zDHHCs and their targets will be set up to expand the range of tools capable of interfering with altered protein S-palmitoylation in AD. To this end, a combination of different in vitro and in vivo techniques (electrophysiology, molecular biology, behavioral tests, microscopy studies) will be used in both animal and human models of AD, concurrent with innovative biotechnological strategies.
Detailed description
S-palmitoylation is a protein post-translational modification involving the attachment of a palmitic acid molecule to cysteine residues. This modification influences protein trafficking toward cellular membranes and is finely regulated by a class of enzymes named zinc finger DHHC domain containing (zDHHC) S-acyltransferases. Proteins critically involved in Alzheimer's disease (AD), such as APP and BACE1, are targets of S-palmitoylation. Higher levels of S-palmitoylated proteins have been found in both post-mortem brain samples and brain organoids derived from induced pluripotent stem cells (hiPSCs) obtained from AD patients. Notably, both neurons and brain organoids derived from human AD hiPSCs exhibited molecular, morphological, and functional alterations reminiscent of AD. Intranasal administration of the palmitoylation inhibitor 2-bromopalmitate (2-BP) significantly counteracted LTP and memory deficits in 3×Tg-AD mice, extended lifespan, and decreased Aß deposition. Higher levels of zDHHC7 and zDHHC21 were also found in the hippocampus of 3×Tg-AD mice. Silencing of zDHHC7 in the hippocampus of 3×Tg-AD mice prevented cognitive deficits and Aß accumulation, along with counteracting palmitoylation of proteins critically involved in neuronal function. This confirms that modulation of zDHHC activity may be exploited for AD treatment.
The idea underlying this project is based on the assumption that zDHHC enzymes and alteration of protein S-palmitoylation play a key role in the onset and progression of AD. Dysregulated zDHHC activity and aberrant S-palmitoylation of neuronal proteins critically involved in the regulation of brain plasticity, neuroinflammation, and Aß metabolism can affect synaptic function, protein homeostasis, and mitochondrial activity, leading to the development of neurodegeneration and cognitive deficits. A druggable target, zDHHC7, has been identified to test the efficacy of novel therapeutic approaches. This study aims to validate a new strategy targeting zDHHC enzymes in human experimental models of AD. Human models will allow an understanding of the translation potential of these approaches to human disease, to be validated in subsequent clinical trials whose implementation exceeds the duration of the present project.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Alzheimer's disease patients | – | Other: Palmitoylation Enzyme Expression Profiling StudyTO DETERMINE THE EXPRESSION OF zDHHC ENZYMES AND CHANGES OF PROTEIN S- PALMITOYLATION IN THE hiPSC-DERIVED NEURONS AND BRAIN ORGANOIDS OBTAINED FROM AD PATIENTS |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- The study population will be drawn from adults receiving care at Clinica della Memoria at Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome, Italy
Key inclusion criteria (3 listed)
- Clinical diagnosis of Alzheimer's Disease
- Age between 18 and 80 years
- Signed informed consent obtained
Key exclusion criteria (5 listed)
- Patients suffering from other neurological diseases;
- Patients with coagulation disorders or in treatment with anticoagulant drugs;
- Patients suffering from dermatological diseases and connective tissue diseases;
- Patients suffering from other organic, psychiatric diseases or laboratory abnormalities could preclude participation or invalidate the study results;
- Inability to give informed consent.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Palmitoylation Enzyme Expression Profiling StudyThe expression of 23 zDHHC enzymes will be studied in human post-mortem hippocampi of AD patients and controls that have already been collected from UK brain biobanks. zDHHC enzymes will be analyzed at both mRNA and protein levels by Real Time PCR and Western blotting techniques, respectively | Other | Alzheimer's disease patients |
Primary outcome
Differences in zDHHC mRNA and protein expression levels between Alzheimer's disease (AD) models and control samples
Time frame: Year 1
Levels of zDHHC enzymes will be quantified in AD models and controls to measure potential differences. Real-Time PCR will be used to assess mRNA expression, while Western blotting will measure protein levels, providing detailed profiles of zDHHC expression.
Change in AD-associated deficits following zDHHC7 downregulation
Time frame: Year 1
Measurable changes in AD-associated deficits will be assessed after zDHHC7 downregulation, with a focus on alterations in cellular or molecular markers relevant to Alzheimer's pathology.
1 secondary outcome
Decrease in zDHHC enzyme expression in human experimental models of Alzheimer's disease
Time frame: Year 2
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Nov 2024.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Claudio Grassi principal investigator
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Alzheimer Disease, run by Fondazione Policlinico Universitario Agostino Gemelli IRCCS at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 7 Nov 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Claudio Grassi (+390630154966, claudio.grassi@policlinicogemelli.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Differences in zDHHC mRNA and protein expression levels between Alzheimer's disease (AD) models and control samples (time frame: Year 1). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Nov 2024.