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Information on APP normal function and Alzheimer's Disease 

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Information on APP normal function and Alzheimer's Disease 

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The APP gene provides instructions for making a protein called amyloid precursor protein. Learn about this gene and related health conditions.

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Strength:

Selective gene editing approach that edits the APP while maintaining its neurophysiological functions

Experiment in performed in both in cultured cells and in mouse

Experiment was performed in an “AD-like setting”

Multiple experiments performed to confirm that APP C-terminus was edited without off target effects

Weakness:

There is no data for the long term effects of this editing strategy so the preservation of the physiological function in the long term can not be concluded.

The off target effects analyzed in this experiment could not detect the small Double Stranded DNA breaks.

Although the experiment was performed in an “AD-like setting” and in-vitro, the significance of this experiment for in vivo Alzheimer's can not be determined until further experiments are performed.

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Maintaining the normal functions of the endogenous proteins as it is responsible for the physiological roles.

Ensuring there are no off target effects

Maintaining the function of N-terminus as the goal of this experiment was to edit only the C-terminus of APP

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Amyloidogenic pathway and Non-amyloidogenic pathway. (Sun et al., 2015)

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Using Crispr/Cas9 techniques to selectively edit the amyloid precursor protein (APP) at the extreme C-terminus, the authors were able to manipulate the amyloid pathway by decreasing the APP-β-cleavage and Aβ production, while up-regulating APP-α-cleavage. This is a significant finding as APP is linked to many different neurodegenerative diseases such as Autism, fragile X syndrome and many more. The selective editing techniques can be used in creating a gene therapy for neurodegenerative diseases. (Vu Nguyen, K., 2019)

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Figure 5: Mechanistic details of CRISPR-guided APP editing. (Sun et al., 2019)

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Experiment 4: The mechanism of CRISPR guided editing of the APP C-terminus and manipulation of α/β cleavage

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Experiment 4: The mechanism of CRISPR guided editing of the APP C-terminus and manipulation of α/β cleavage

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Main Finding: There was less interaction between APP and BACE-1 for the AAV9-sgRNA transfected neurons.

In the interaction of APP/BACE-1 between the wildtype and the AAV9-sgRNA transfected neurons, the fluorescence is detected much more in the wildtype compared to the transfected neurons which indicates that there was less interaction between APP and BACE-1.

The internalization assay showed that APP are mostly internalized into endosomes in WT neurons; where as APP in APP659 (crispr-mimicking) neurons mostly remains in plasma membrane, suggesting that C-terminal truncation likely attenuates β-cleavage by preventing APP internalization.

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Figure 4: Gene editing of APP C-terminus in vivo. (Sun et al., 2019)

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Experiment 4: In vivo editing of the APP C-terminus

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Experiment 4: In vivo editing of the APP C-terminus

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Main Finding: The mo-APP-sgRNA has successfully edited the C-terminus in vivo (mouse)

Immunostaining with the APP Y188 antibody was performed, and there wasless fluorescence in the APP-sgRNA transfected mouse compared to Cas9 only and uninfected mouse. This shows the evidence of APP editing in vivo in mouse.

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Figure 3: Effect of APP C-terminus editing on neuronal physiology. (Sun et al., 2019)

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Experiment 3: Neurophysiology effects of editing the APP and the analysis of off targets

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Experiment 3: Neurophysiology effects of editing the APP and the analysis of off targets

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Main Finding: No significant effect was detected for the editing of APP C-terminus on the N-terminus neuronal physiology.

In the cultured neurons, both cas9 only and mo-APP-sgRNA had similar results for the N-terminal but the neurons transfected with AAV9-Cas9 had higher Y188 antibody in the CTFs compared to the neurons transfected with AAV9-sgRNA.

The normalized axon length has no significant difference for both the Cas9 only and the mo-APP-sgRNA.

The cas9 only and mo-APP-sgRNA transfected neurons were stained with the presynaptic marker VAMP2. The presynaptic density was compared for the mo-APP-sgRNA and Cas9 only transfected neurons, the result had no significant difference. This indicates that there is no significant neuronal physiological difference between the edited and unedited APP C-terminus.

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Figure 2: Gene editing of APP C-terminus and effects on APP processing in human cells. (Sun et al., 2019)

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Experiment 2: The editing of APP C-terminus and the effects on the β/α pathway in human cells

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Experiment 2: The editing of APP C-terminus and the effects on the β/α pathway in human cells

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Main Finding: The editing of the APP has reciprocal effects on β/α cleavage as the editing results in upregulation of α cleavage and downregulation of β cleavage

Human iPSC derived neurons were immunostained with the Y188 and tubulin antibodies, the APP expression is higher in the Control-sgRNA compared to hu-APP-sgRNA. This indicates that hu-APP-sgRNA has edited the APP C-terminus in human iPSC derived neurons.

In both the WT and London mutation group, there is an upregulation of sAPPα for the hu-APP-sgRNA transfected cells compared to control-sgRNA which indicates the upregulation of non-amyloidogenic pathway.

In both the WT and London mutation group, when ELISA and western blot was performed, there is a downregulation of sAPPβand Aβ 40/42 for the hu-APP-sgRNA transfected cells compared to control-sgRNA. This indicated the downregulation of the amyloidogenic pathway.

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Figure 1. Manipulation of the amyloid pathway by CRISPR/Cas9 editing. (Sun et al., 2019)

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Experiment 1: .Using CRISPR/Cas9 editing to the APP C-terminus and manipulate the amyloid pathway in mouse cells

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Experiment 1: .Using CRISPR/Cas9 editing to the APP C-terminus and manipulate the amyloid pathway in mouse cells

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Main finding: mo-APP-sgRNA has selectively edited the C-terminus of the APP without affecting the N-terminus.

Significantly less Y188 C-terminus antibody signals in the neuro2a cells that are transfected with mouse-APP-sgRNA compared to cas9 only.

Significantly less CTFs signal in the mo-APP-sgRNA compared to the control-sgRNA but the signals in the N-terminus remained the same.

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1. Cholinesterase inhibitors:

AD patients have lower level of acetylcholine. Cholinesterase inhibitors can prevent breakdown of acetylcholine.

2. NMDA receptor antagonists:

AD patients have excess glutamate signalling. NMDA receptor antagonists can decrease glutamate signalling by blocking their receptors.

Both approaches can only temporarily ease AD symptoms, but are not cures for AD.

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https://alzheimer.ca/en/about-dementia/how-can-i-treat-dementia/medications-approved-treat-alzheimers-disease

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Which medication can help you?

Medications to treat Alzheimer's may slow the rate of cognitive decline, or help with symptoms such as changes in language, thinking abilities and movement.

Each medication has a brand name and a generic name.

Aricept™ (brand name) or Donepezil (generic name)

Reminyl ER™ (brand name) or Galantamine (generic name)

Exelon™ (brand name) or Rivastigmine (generic name)

Ebixa® (brand name) or Memantine (generic name)

For the purpose of your treatment, it doesn't matter whether the medication is brand name or generic - their effects are the same.

Depending on how severe your symptoms are and how quickly the disease progresses, different medications may be appropriate.

Medications for mild to moderate Alzheimer's:

Donepezil (Aricept™)

Galantamine (Reminyl™)

Rivastigmine (Exelon™)

Medications for moderate to advanced Alzheimer's disease:

Memantine (Ebixa®)

Donepezil (Aricept™)

How do these medications work?

Three of them can help prevent decline in learning and memory

Three of the medications - donepezil (Aricept™), galantamine (Reminyl™) and rivastigmine (Exelon™) - are cholinesterease inhibitors. These medications are can prevent the breakdown of a brain chemical called acetylcholine.

Understand more about acetylcholine:

Acetylcholine is a chemical in the brain thought to be important for learning and memory.

A person with Alzheimer's has lower levels of acetylcholine than someone without the disease.

By providing an increased concentration of acetylcholine, these medications may temporarily ease or stabilize some of the symptoms of Alzheimer's.

These medications may be helpful for two to three years, possibly longer. Eventually, the nerve endings die and the medications are no longer effective. Because of that, they are only useful for people in the mild to moderate stages of dementia.

One of them can protect your brain cells

The other medication, memantine (Ebixa ®), is an NMDA receptor antagonist. This medication is thought to work by affecting another brain chemical called glutamate.

Understand more about glutamate:

Glutamate helps send messages between brain cells.

Glutamate is released in excessive amounts when brain cells are damaged by Alzheimer's.

Memantine may protect brain cells by blocking effects of too much glutamate.

Some specialists recommend adding memantine to one of the cholinesterase inhibitors once a person with Alzheimer's has progressed from the early and middle stages to the middle and late stages.

Memantine can be prescribed for people in the middle and late stages who can't tolerate the side effects from a cholinesterase inhibitor.

How can you tell if a medication is helping or hurting?

Potential improvements

Improvements are often subtle and can be hard to detect, even for your doctor or pharmacist. It also may take several months to see the benefits. Some people will benefit more than others.

Improvements may include:

Modest cognitive changes: The person living with Alzheimer's notices improvements in memory, concentration and language.

Subtle behavioural changes: The person living with Alzheimer's is calmer, more engaged in daily activities (such as cooking, bathing and using appliances), more motivated and more communicative.

Some people will not show significant improvement, but they may stabilize for a period of time.

Potential side effects

Medications are usually started at the lowest dose available, which may help minimize side effects. If the person is tolerating the medication, the dosage is usually increased slowly to maximize the benefits of the treatment.
If any of these side effects are experienced, contact your doctor or pharmacist as soon as possible.
Side effects of donepezil, galantamine and rivastigmine:

Gastrointestinal side effects, like nausea, vomiting, diarrhea or loose stools,

Loss of appetite and subsequent unintended weight loss,

Slowing of heart rate,

Dizziness,

Falls,

Headaches and

Nightmares,

Side effects of memantine:

Caution is also required in prescribing memantine for people who have problems with their kidneys.

No changes

Because Alzheimer's is a progressive disease that gets worse over time, noticing no changes in the person's daily function and behaviour for six months or a year after starting the drug is a positive outcome and a sign that the medication is working.

If the medications are discontinued, the person may lose the benefits and might decline at a rate faster than otherwise expected.

When should you start taking these medications?

If there are no other health conditions that could make taking these medications dangerous for you, doctors generally recommend starting a trial of one of the cholinesterase inhibitors immediately after diagnosis.

If your family doctor is uncomfortable or reluctant to prescribe one of these medications, consider requesting a consultation with a geriatric specialist for another opinion.

For how long should these medications be taken?

If you are benefiting from the medication and can tolerate the side effects, it's often recommended that you continue taking the medication until the final stages.

In other cases, where there is no clear benefit, if there is a safety concern, the side effects are too difficult, or you may just dislike taking the medication, then it may be time to stop treatment. Each experience is unique - consult your doctor to decide what's best.

Are these medications effective for other types of dementia?

Cholinesterase inhibitors (donepezil, galantamine and rivastigmine) were originally developed to treat only Alzheimer's disease, not for other types of dementia and similar conditions such as mild cognitive impairment (MCI).

However, there may be some cases where these medications are effective, depending on the type of dementia:

Cholinesterase inhibitors, particularly donepezil and rivastigmine, are also commonly used to treat dementia with Lewy bodies and have been reported to reduce visual hallucinations.

Rivastigmine has also been approved to treat dementia brought on by Parkinson's disease.

There is not enough evidence that supports the use of cholinesterase inhibitors or memantine in people living with vascular dementia or frontotemporal dementia.

However, for people with a combination of Alzheimer's disease and vascular dementia (known as mixed dementia), cholinesterase inhibitors may be used when Alzheimer's disease is the main cause, but not to treat vascular dementia on its own.

In the case of MCI, these medications are generally not effective. They do not reduce the risk of MCI progressing to Alzheimer's disease or another type of dementia.

Important to know:

Dementia affects each person differently. A treatment that works for one person may not work for someone else.

Are these medications covered by your provincial health insurance plan?

Medication coverage varies from province to province and individuals may be required to cover some of the costs associated with these medications.

The person must meet specific criteria in their province to be entitled to have the medications paid for by their provincial medical coverage plan. Check with your province's health plan to find out if you have coverage.

Medication may also be covered by many private insurance plans.

What other treatment options are available?

Medications should only be one part of your overall care. Consider your treatment options:

Some alternative treatments (such as music therapy, aromatherapy, pet therapy, and massage) may be beneficial to people with dementia. However, the lack of evidence supported by research prevents us from determining their effectiveness.

There are potential treatments that may be effective in treating not just the symptoms of Alzheimer's, but perhaps even stop cognitive decline outright. However, plenty of research and testing needs to be done to validate their results. We may still be years away from seeing these new treatments become available to the public.

The most effective treatment that doesn't involve medication? Follow a brain-healthy lifestyle. Taking part in physical and social activities, challenging your brain and making healthy choices are vital to living well with dementia.

For a full list of treatment options currently available to you, please read our print-friendly brochure. Now that you know the accurate information and realistic expectations about the potential benefits and possible side effects of these medications, talk with your doctor or pharmacist about whether these medications are right for you.
More useful links and resources

Medications for Alzheimer's disease: Are they right for you? Alzheimer Society of Canada. Get all the information you need on the current medications approved to treat the symptoms of Alzheimer's disease, including their potential benefits and risks.

What is aducanumab? Alzheimer Society of Canada. This information page summarizes information about a drug that was conditionally approved for use in the United States in June 2021. A European Union agency refused the drug in December 2021. Drug-maker Biogen withdrew the drug from Health Canada review in June 2022.

Drug approval process for the treatment of Alzheimer's disease. Alzheimer Society of Canada. Get the full picture of how a drug gets approved for public use in Canada, including a list of the currently approved medications that can treat the symptoms of Alzheimer's.

Treatment options. Alzheimer Society of Canada. This downloadable brochure gives an overview of all the treatment options for Alzheimer's that are available to you.

Canada's provincial health plans. Special Benefits Insurance Services. This page is a helpful summary of the covered healthcare services in each province, with links to each plan on each respective province's government website.

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Medications approved to treat Alzheimer's disease

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Medications to treat Alzheimer's may slow the rate of cognitive decline, or help with symptoms such as changes in language, thinking abilities and movement. Each medication has a brand name and a generic name.

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https://alzheimer.ca/en/about-dementia/what-alzheimers-disease
The Alzheimer's Disease (AD) is a neurodegenerative disease commonly acquired in mid-life or late-life. The common symptoms of AD include impairment in memory, expressive speech, visuospatial processing and executive functions. (Knopman et al., 2021)

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We've only recently identified Alzheimer's as a serious and prevalent disease

Alzheimer's disease has been with us throughout human history. However, our understanding of it has been relatively recent:

In the last 100 years: Alzheimer's disease has been formally identified and named;

In the last 50 years: We've made serious advances to recognize the impact of Alzheimer's, and commit to finding treatments and a cure; and

In the last 20 years: We've taken more steps to fight the stigma against the disease and support the voices of people living with Alzheimer's, families and caregivers.

Plenty of progress has been made, and we still have ways to go.
Read more about the history behind Alzheimer's disease.
Alzheimer's disease is the most common type of dementia

Alzheimer's disease is the most common type of dementia, accounting for 60 to 80% of all diagnoses.

However, it's not accurate to say that if a person has dementia, then they have Alzheimer's disease - or that all dementias are a form of Alzheimer's.
Know the difference between Alzheimer's disease and dementia.
Alzheimer's disease changes the brain

Alzheimer's disease is a fatal disease that eventually affects all aspects of a person's life - how they think, feel and act.

Each person is affected differently. While it's difficult to predict symptoms, the order in which they will appear or the speed of their progression, there are some warning signs you can look out for.
Learn more about how Alzheimer's disease changes the brain.
Alzheimer's disease is progressive

Alzheimer's disease is usually described in terms of stages, indicating the severity of the symptoms.

Early stage: Symptoms are mild. A person at this stage is fully aware of their condition and only needs minimal assistance, if requested.

Middle stage: Symptoms start becoming more noticeable. More assistance will be needed to help the person living with Alzheimer's accomplish daily tasks.

Late stage: Once the person reaches this stage, they will eventually become unable to communicate verbally or look after themselves. Quality of care is important to ensure that the person has quality of life.

End-of-life: Cognitive decline has progressed to the point where the person needs 24-hour care. The focus shifts to palliative care and comfort to ensure quality of death.

The earlier on in the disease that a person gets diagnosed, the higher the chances are for a better quality of life while having the disease.
Learn more about the different stages of Alzheimer's disease.
Having family with Alzheimer's doesn't mean you will also get it

Most cases of Alzheimer's disease are sporadic, meaning they do not run in families.

Only rare instances of Alzheimer's disease are inherited or familial, accounting for less than five percent of all cases. There is genetic testing available for families that have a history of this form of Alzheimer's.
Learn more about the genetics behind Alzheimer's disease.
You can reduce your risk of Alzheimer's disease

Reducing your risk by making brain-healthy lifestyle choices won't guarantee you won't get Alzheimer's, but it's still the most effective method of prevention.

Other alleged methods have not held up to scientific study, and more research needs to be done to conclusively show their effects.
Learn more about the risk factors for dementia.
The symptoms of Alzheimer's disease can be treated, but not cured...yet

There are several medications that can help with symptoms such as memory decline, changes in language, thinking abilities and motor skills.

Although there is still no cure for Alzheimer's disease, those who respond to these treatments can experience improvements in their quality of life for several years.

Researchers continue to search for more effective treatments for Alzheimer's as well as as a cure. Thanks to their efforts, our understanding of Alzheimer's disease and other dementias become clearer with each day.
Learn more about the medications available to treat Alzheimer's disease.
You can still live well with Alzheimer's

If you've been recently diagnosed, first know that there are resources and help that are available to support you and your family.

While every journey is unique, and it will be difficult, know that there are people who live well with Alzheimer's disease and other dementias.

Research shows that there are many things that can help you live well with living with Alzheimer's disease. Making healthy lifestyle choices may help slow the progression of the disease and make it easier to manage the changes that the disease brings.

By getting the support you need as quickly as possible, you can maintain a high quality of life while living with the disease for as long as possible.
Find out what steps to take after diagnosis.
More useful links and resources

What is Alzheimer's disease? Alzheimer Society of Canada. This print-friendly, downloadable brochure gives an overview of what Alzheimer's disease is, including what we know so far from research, its effects and risk factors.

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Alzheimer's disease has been with us throughout human history. However, our understanding of it has been relatively recent: In the last 100 years: Alzheimer's disease has been formally identified and named; In the last 50 years: We've made serious advances to recognize the impact of Alzheimer's, and commit to finding treatments and a cure; and In the last 20 years: We've taken more steps to fight the stigma against the disease and support the voices of people living with Alzheimer's, families and caregivers.

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BifC Assay Design (Image created in BioRender.com) (Sun et al., 2019)

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Experiment 4: Investigation of APP β/α manipulation mechanisms in vivo (Fig.4, 5)

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Experiment 4: Investigation of APP β/α manipulation mechanisms in vivo (Fig.4, 5)

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Experimental Groups:

1. APP-659: CRISPR-mimicking (truncated C-terminus) construct

2. APP-T668A: mutation in APP C-terminal T668 residue

Normal function of T668: co-localization with BACE1

3. APP-YENPTY: mutation in APP C-terminal YENPTY motif

Normal function of YENPTY: internalization of APP into endosomes

Methods:

1. AAV9 carrying sgRNA delivered to neonatal mouse hippocampus / ventricles

2. Y188 immunostaining: confirmation of CRISPR/Cas9 editing (Fig.4)

3. BifC (Bi-molecular Fluorescence Complementation) assay: visualization of APP-BACE1 interaction (Fig.5a-d)

4. Internalization assay (APP N-terminus immunostaining) (Fig.5e)

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T7 endonuclease assay design (Image created in BioRender.com) (Sun et al., 2019)

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Experiment 3: Analysis of off-target & deleterious effects (Fig.3)

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Experiment 3: Analysis of off-target & deleterious effects (Fig.3)

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Methods:

1. Off-target analysis by T7 endonuclease assay

Result: no CRISPR-editing in top 5 predicted off-target sites

2. Analysis in normal physiological roles of APP in cultured mouse hippocampus neurons:

neurite outgrowth, axon-length, synaptic organization, or neuronal activity

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Indirect ELISA design (Image created in BioRender.com) (Hornbeck et al., 2001)

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Experiment 2: Examination of effect of APP truncation in β/α pathways (Fig.2)

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Experiment 2: Examination of effect of APP truncation in β/α pathways (Fig.2)

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Experimental groups: human iPSC-derived cell lines

WT/WT: wild type (control)

WT/APPLondon: AD phenotype

Methods:

1. Immunostaining of APP C/N-terminus

2E9: APP N-terminus antibody

Y188: APP C-terminus antibody

2. Western blot of sAPPα (product of α-cleavage)

3. ELISA (enzyme-linked immunosorbent assay) of β-pathway:

Concentration of target molecule (antigen) measured by colour-change/fluorescence level.

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Visualization targets in experiment 1 (Image created in BioRender.com)(Sun et al., 2019)

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Experiment 1: Confirmation of CRISPR/Cas9 editing at APP C-terminus (Fig.1)

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Experiment 1: Confirmation of CRISPR/Cas9 editing at APP C-terminus (Fig.1)

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Methods:

1. sgRNA selection based on Aβ-attenuating ability: APP-659 sgRNA.

2. Visualizing APP truncation by immunostaining:

22C11: APP N-terminus antibody

Y188: APP C-terminus antibody

3. Analyzing effect of APP C-terminal truncation in β-cleavage pathway by western blot:

CTF (C-terminal fragment): product of APP β-cleavage when γ-secretase is inhibited by GSI (γ-secretase inhibitor)

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Processing pathways of APP (Knopman et al., 2021)(Struyfs et al., 2015)(Sun et al., 2019)

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The aggregation of Amyloid-β (Aβ) plaques is a major neuropathological characteristic of AD (Knopman et al., 2021).

The neuroprotective α-cleavage and pathogenic β-cleavage of APP competitively inhibits each other. β-cleavage of APP predominates when APP is located in the plasma membrane, whereas α-cleavage predominates when APP is internalized into endosomes (Sun et al., 2019).

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1. Apply CRISPR technology in treating neurodegenerative disease. More specifically, attenuate β-cleavage of APP and Aβ production by CRISPR-directed truncation of APP C-terminus.

2. Avoid deleterious effects. More specifically, preserve the normal physiological functions of APP.

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CRISPR/Cas9 guided gene editing (Image created in BioRender.com) (Fellman et al., 2017) (Sun et al., 2019)

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INTRODUCTION: CRISPR/Cas9 guided gene editing

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INTRODUCTION: CRISPR/Cas9 guided gene editing

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Current practical limitations of CRISPR technology:

1. Canonical deletion of an entire gene by NHEJ is very likely to cause deleterious effects (Sun et al., 2019).

2. The procedure of point-mutation correction needs to be designed in mutation-specific basis (Sun et al., 2019).

3. Point-mutation correction only be applied to neurodegenerative diseases that are caused by inherited point mutations, which only covers <10% of all cases. (Sun et al., 2019)

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Atithi Sharma: Results, Discussion, Conclusion, Future Outlook
Haoyu Yang: Introduction, Methods, Future Outlook

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The off target effects analyzed in this experiment could not detect the small Double Stranded DNA breaks. So to further explore that there were no off target effects, more intense analysis that looks at the double stranded breaks thoroughly has to be performed.

The significance of editing the C-terminus of Amyloid Precursor Protein in vivo on Alzheimer’s disease needs to be further explored.

Sun J. has patented their Gene Editing-Based Method of Attenuating the Beta-Amyloid Pathway described in this article.

Roy, S., & Sun, J. (2022). Gene Editing-Based Method of Attenuating the Beta-Amyloid Pathway.

Sun J. continues researching in the underlying mechanisms and potential treatments for AD.

Shen, S., Liao, Q., Wong, Y. K., Chen, X., Yang, C., Xu, C., Sun, J., & Wang, J. (2022). The role of melatonin in the treatment of type 2 diabetes mellitus and Alzheimer’s disease. International Journal of Biological Sciences, 18(3), 983–994. https://doi.org/10.7150/IJBS.66871

Zhang, W., Xu, C., Sun, J., Shen, H.-M., Wang, J., & Yang, C. (2022). Impairment of the autophagy–lysosomal pathway in Alzheimer’s diseases: Pathogenic mechanisms and therapeutic potential. Acta Pharmaceutica Sinica. B, 12(3), 1019–1040. https://doi.org/10.1016/j.apsb.2022.01.008

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Fellmann, C., Gowen, B. G., Lin, P.-C., Doudna, J. A., & Corn, J. E. (2017). Cornerstones of CRISPR-Cas in drug discovery and therapy. Nature Reviews. Drug Discovery, 16(2), 89–100. https://doi.org/10.1038/nrd.2016.238

Hornbeck, P., Winston, S. E., & Fuller, S. A. (2001). Enzyme-linked immunosorbent assays (ELISA). Current Protocols in Molecular Biology (Print), Chapter 11(1), Unit11.2–Unit11.2. https://doi.org/10.1002/0471142727.mb1102s15

Knopman, D. S., Amieva, H., Petersen, R. C., Chételat, G., Holtzman, D. M., Hyman, B. T., Nixon, R. A., & Jones, D. T. (2021). Alzheimer disease. Nature Reviews. Disease Primers, 7(1), 33–33. https://doi.org/10.1038/s41572-021-00269-y

NIH. (n.d.). App gene: Medlineplus genetics. MedlinePlus. Retrieved December 5, 2022, from https://medlineplus.gov/genetics/gene/app/#conditions

Struyfs, H., Van Broeck, B., Timmers, M., Fransen, E., Sleegers, K., Van Broeckhoven, C., De Deyn, P. P., Streffer, J. R., Mercken, M., & Engelborghs, S. (2015). Diagnostic Accuracy of Cerebrospinal Fluid Amyloid-beta Isoforms for Early and Differential Dementia Diagnosis. Journal of Alzheimer’s Disease, 45(3), 813–822. https://doi.org/10.3233/JAD-141986

Sun, J., Carlson-Stevermer, J., Das, U., Shen, M., Delenclos, M., Snead, A. M., Koo, S. Y., Wang, L., Qiao, D., Loi, J., Petersen, A. J., Stockton, M., Bhattacharyya, A., Jones, M. V., Zhao, X., McLean, P. J., Sproul, A. A., Saha, K., & Roy, S. (2019). CRISPR/Cas9 editing of App C-terminus attenuates β-cleavage and promotes α-cleavage. Nature Communications, 10(1). https://doi.org/10.1038/s41467-018-07971-8

Sun, X., Chen, W.-D., & Wang, Y.-D. (2015). Β-amyloid: The key peptide in the pathogenesis of alzheimer’s disease. Frontiers in Pharmacology, 6. https://doi.org/10.3389/fphar.2015.00221

Vu Nguyen, K. (2019). Β-amyloid precursor protein (APP) and the human diseases. AIMS Neuroscience, 6(4), 273–281. https://doi.org/10.3934/neuroscience.2019.4.273

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CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage

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The strategy of selective editing shows hopeful results as the authors were able to target and edit only the C-terminus of the APP. The CRISPR guided editing of the C-terminus resulted in the upregulation for the neuroprotective non-amyloidogenic pathway that might be used for the treatment of neurodegenerative disorders like Alzheimers.