The Strategies for Treating “Alzheimer’s Disease”: Insulin Signaling May Be a Feasible Target

Round 1

Reviewer 1 Report

The mutations in amyloid precursor protein (APP), presenilin 1/2, and ADAM10 have been linked the Ab-oxidative stress- immune activation induced propagation of brain inflammation and neurodegeneration in the Alzheimer’s disease (AD). Based on the observation of insulin deficiency and the resulting higher levels of glucose in cerebrospinal fluid (CSF) and the blunt of insulin signaling in the PD patients, You et al in the current review paper (The strategies of treating “Alzheimer’s disease”: preventing insulin resistance maybe feasible at early stage) provided the update information about the role of insulin defects and its impact in the progress of AD.  Overall, the result of this review paper suggests that insulin deficiency/resistant could triggers Ab and/or tau -induced AD pathology. Overall, the information provided in the paper is confusing and need the recommended modifications.

 

 

It is suggested that the histopathological characters of AD are defined by extracellular deposits of amyloid-beta and intracellular neurofibrillary tangles (NFT) formed by hyperphosphorylated tau protein.   It is also stated that the efficient insulin supply may prevent or postpone the initiation of tau pathology in earlier stage of AD. However, in later stage of AD, it may be more decent to relieve the inflammation and hold back the propagation of tau and its adverse effects but the supportive explanations and figures do not provide a clear link between Insulin defect – extracellular deposits of amyloid-beta and intracellular formation of   hyperphosphorylated tau protein and their impact altering the neuro protective/destructive states (brain inflammation, neurodegeneration, and cognitive defects) in AD. The Authors need to provide clear path and the exact mechanistic figures for   the indicated explanations

 

Abstract is  full of English and grammatical errors, (e.g., Many mutations in amyloid precursor protein (APP), presenilin 1/2 and ADAM10 have be identified in  familial AD, raising the amyloid cascade hypothesis that emphasized the accumulation of Ab triggered oxidative stress, immunoreaction, et. al, and most importantly the tau pathology.),which needed extensive revision and corrections stated that .  

 

Introduction are full of English and grammatical errors and needs extensive revisions in English and grammar ( See below the  some examples).  

Alzheimer’s disease (AD) is known as the most common form of dementia that oc-27 curs along with aging. The histopathological characters of AD are defined by extracellular 28 deposits of amyloid-beta (A) and intracellular neurofibrillary tangles (NFT) formed by 29 hyperphosphorylated tau protein. Apparently, the initiation of AD is closely associate 30 with the extent of A loading, as evidenced by familial AD cases, who carrying the muta-31 tions in amyloid precursor protein (APP) and/or presenilin-1/2 (PS1/2, the components of 32 -secretase) that lean to result in the accumulation of A plaques, probably suffer AD dur-33 ing their early life.

 

There is a lack of link between (While, the degree of dementia is stronger correlated with NFT burden 34 rather than A senile plaques [1]).  And (According to the pathological staging of AD descripted 35 by Braak et. al in 1991 [2], the emergence of NFT was specifically found in the entorhinal 36 cortex and hippocampus, and spread subsequently to other area of cortexes at the end-37 stages of AD).

 

Figure 1. The probable linkage within A insulin deficiency/resistance, microglia/inflammation 64 and tau pathology in AD. The constantly production of A needs to be eliminated by microglia 65 through endocytosis and/or by the drainage of micro-vessels. However, the activation of microglia 66 resulted in the secretion of cytokines which will perturb the function of endothelial cell in blood-67 brain barrier. The overloading of A plus inflammatory cytokines lead to the impairment of brain-68 blood barrier permeability (provide the  related figure , including the transport of insulin from peripheral to brain. The defi-69 ciency  and resistance ( how the  insulin deficiency and resistance can happens together; provide the figure) of insulin further trigger the phosphorylation of tau  ( Explain how does this happen  and provide  figure showing the the predicted pathway between  Insulin defect -  pTau) and subsequent the im-70 pairment of mitochondrial ( mitochondrial what??????????). The tau pathology could be propagated via the synapse and exosome in 71 a microglia dependent manner, which eventually leading to the neural cell death (Provide clear path of indicated pathology).

 

Modify the Table 1 and the related lines 104 – 155 by providing the therapeutic approaches that reduce the Ab accumulation as well as their side effects in both mouse model and patients with AD.

  

Figure 2 is confusing; re design it.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

In this review, You et al. laid efforts to recall the attention to the ALDs. Particularly, they focused on discussing the strategy of using insulin resistance at the early stage of ALDs, which may be potentially important in preventing this severe disease.

 

The review was organized nicely with an easy-reading logic by introducing the direct causes of Ads followed by the current and potential treatments. Through deep discussions about restricting amyloid-beta overproduction, insulin resistance, tau pathology, and anti-inflammation, they proposed the efficient insulin supply at the early stage of AD may be helpful to the treatment of ALDs. I think the manuscript can be accepted, but there is one issue that should be noted.

 

There are many grammatical issues, and though I am not a native speaker, I noticed quite a lot. I would suggest the authors paying more attentions in writing. I just listed a few of the problematic sentences (they are many more in the manuscript):

In abstract (almost more than half of contents have grammatical problem):

Along with severe disability of learning and memory, and neuron atrophy to different extant.

Many mutations in amyloid precursor protein (APP), presenilin 1/2 and ADAM10 have be identified in familial AD

However, the linkage between Ab and subsequent tau pathology in this proposal remain unclear.

The AD was also suggested to be type-3 diabetes, since the observation of insulin deficiency and the high level of glucose in cerebrospinal fluid (CSF), and the blunt of insulin signaling in the patients.

 

In introduction:

Line 31-32: …, who carrying the mutations in amyloid precursor protein (APP) and/or presenilin-1/2 (PS1/2, the components of …

Author Response

Response to Reviewer 1 Comments

 

In this review, You et al. laid efforts to recall the attention to the ALDs. Particularly, they focused on discussing the strategy of using insulin resistance at the early stage of ALDs, which may be potentially important in preventing this severe disease.

 

Point 1:

The review was organized nicely with an easy-reading logic by introducing the direct causes of Ads followed by the current and potential treatments. Through deep discussions about restricting amyloid-beta overproduction, insulin resistance, tau pathology, and anti-inflammation, they proposed the efficient insulin supply at the early stage of AD may be helpful to the treatment of ALDs. I think the manuscript can be accepted, but there is one issue that should be noted.

Response 1: We appreciate this comment very much.

Point 2:

There are many grammatical issues, and though I am not a native speaker, I noticed quite a lot. I would suggest the authors paying more attentions in writing. I just listed a few of the problematic sentences (they are many more in the manuscript):

In abstract (almost more than half of contents have grammatical problem):

Along with severe disability of learning and memory, and neuron atrophy to different extant.

Many mutations in amyloid precursor protein (APP), presenilin 1/2 and ADAM10 have be identified in familial AD

However, the linkage between Ab and subsequent tau pathology in this proposal remain unclear.

The AD was also suggested to be type-3 diabetes, since the observation of insulin deficiency and the high level of glucose in cerebrospinal fluid (CSF), and the blunt of insulin signaling in the patients.

Response 2: We appreciate this comment very much. The abstract has been rewritened as below.

Alzheimer’s disease (AD) is a neurodegenerative disorder, which is characterized by senile plaques formed by amyloid-beta (Ab) extracellularly and neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau protein intracellularly. Apart from these two features, insulin deficiency and insulin resistant have also been observed in AD brains. Thus, AD has also been referred to as type-3 diabetes by some of the scientists in this field. Insulin plays pivotal role in learning and memory, and is involved in regulating tau phosphorylation though PI3K-Akt-GSK3b signaling pathway. Interestingly, recent studies revealed that in AD brains the microglia transformed into diseased associated microglia (DAM) status in a TREM2 dependent manner to restrain the toxicity of Ab and propagation of tau. Which also correlated with PI3K-Akt signal through the adaptor of TREM2. Whether insulin have any effects on microglia activation in AD pathology is unclear so far. However, many studies demonstrated that diabetes increased the risk of AD. In this review, we summarized the main strategies for curing AD, including lowing the level of Ab, suppressing the phosphorylation of tau, ablation and/or repopulation of microglia, and especially the supply of insulin. We also proposed that the attention should be given to the influences of insulin on microglia in AD.

Point 3:

In introduction:

Line 31-32: …, who carrying the mutations in amyloid precursor protein (APP) and/or presenilin-1/2 (PS1/2, the components of …

Response 3: We appreciate this comment very much. This sentence in introduction has been rewritened as below.

Apparently, the initiation of AD is closely associate with the extent of Ab production, as evidenced by familial AD cases, those who carrying the mutated amyloid precursor protein (APP) and/or presenilin-1/2 (PS1/2, the components of g-secretase) lean to acquire accumulation of Ab plaques in brain, and probably suffer AD earlier.

Round 2

Reviewer 1 Report

Dear Authors,

You have done good job responding and addressing all my comments in the MS. I therefore recommend acceptance of your paper.

Congratulations for this success!