Regional differences in islet amyloid deposition in the residual pancreas with new-onset diabetes secondary to pancreatic ductal adenocarcinoma

BACKGROUND Islet amyloid deposition and reducedβ-cell mass are pathological hallmarks in type 2 diabetes mellitus subjects.To date,the pathological features of the islets in diabetes secondary to pancreatic ductal adenocarcinoma(PDAC)have not been specifically addressed.AIM To provide further insight into the relationship between islet amyloid deposition of the residual pancreas in PDAC patients and to explore whether regional differences(proximal vs distal residual pancreas)are associated with islet amyloid deposition.METHODS We retrospectively collected clinical information and pancreatic tissue removed from tumors of 45 PDAC patients,including 14 patients with normal glucose tolerance(NGT),16 patients with prediabetes and 15 new-onset diabetes(NOD)patients diagnosed before surgery by an oral glucose tolerance test at West China Hospital from July 2017 to June 2020.Pancreatic volume was calculated by multiplying the estimated area of pancreatic tissue on each image slice by the interval between slices based on abdominal computer tomography scans.Several sections of paraffin-embedded pancreas specimens from both the proximal and/or distal regions remote from the tumor were stained as follows:(1)Hematoxylin and eosin for general histological appearance;(2)hematoxylin and insulin for the determination of fractionalβ-cell area(immunohistochemistry);and(3)quadruple insulin,glucagon,thioflavin T and DAPI staining for the determination ofβ-cell area,α-cell area and amyloid deposits.RESULTS Screening for pancreatic histologic features revealed that duct obstruction with islet amyloid deposition,fibrosis and marked acinar atrophy were robust in the distal pancreatic regions but much less robust in the proximal regions,especially in the prediabetes and NOD groups.Consistent with this finding,the remnant pancreatic volume was markedly decreased in the NOD group by nearly one-half compared with that in the NGT group(37.35±12.16 cm^(3) vs 69.79±18.17 cm^(3),P<0.001).As expected,islets that stained positive for amyloid(islet amyloid density)were found in the majority of PDAC cases.The proportion of amyloid/islet area(severity of amyloid deposition)was significantly higher in both prediabetes and NOD patients than in NGT patients(P=0.002;P<0.0001,respectively).We further examined the regional differences in islet amyloid deposits.Islet amyloid deposit density was robustly increased by approximately 8-fold in the distal regions compared with that in the proximal regions in the prediabetes and NOD groups(3.98%±3.39%vs 0.50%±0.72%,P=0.01;12.03%vs 1.51%,P=0.001,respectively).CONCLUSION In conclusion,these findings suggest that robust alterations of the distal pancreas due to tumors can disturb islet function and structure with islet amyloid formation,which may be associated with the pathogenesis of NOD secondary to PDAC.

Repetitive transcranial magnetic stimulation in Alzheimer’s disease:effects on neural and synaptic rehabilitation

Alzheimer’s disease is a neurodegenerative disease resulting from deficits in synaptic transmission and homeostasis.The Alzheimer’s disease brain tends to be hyperexcitable and hypersynchronized,thereby causing neurodegeneration and ultimately disrupting the operational abilities in daily life,leaving patients incapacitated.Repetitive transcranial magnetic stimulation is a cost-effective,neuro-modulatory technique used for multiple neurological conditions.Over the past two decades,it has been widely used to predict cognitive decline;identify pathophysiological markers;promote neuroplasticity;and assess brain excitability,plasticity,and connectivity.It has also been applied to patients with dementia,because it can yield facilitatory effects on cognition and promote brain recovery after a neurological insult.However,its therapeutic effectiveness at the molecular and synaptic levels has not been elucidated because of a limited number of studies.This study aimed to characterize the neurobiological changes following repetitive transcranial magnetic stimulation treatment,evaluate its effects on synaptic plasticity,and identify the associated mechanisms.This review essentially focuses on changes in the pathology,amyloidogenesis,and clearance pathways,given that amyloid deposition is a major hypothesis in the pathogenesis of Alzheimer’s disease.Apoptotic mechanisms associated with repetitive transcranial magnetic stimulation procedures and different pathways mediating gene transcription,which are closely related to the neural regeneration process,are also highlighted.Finally,we discuss the outcomes of animal studies in which neuroplasticity is modulated and assessed at the structural and functional levels by using repetitive transcranial magnetic stimulation,with the aim to highlight future directions for better clinical translations.

Imaging and Spectral Characteristics of Amyloid Plaque Autofluorescence in Brain Slices from the APP/PS1 Mouse Model of Alzheimer’s Disease

Amyloid deposits are one of the hallmark pathological lesions of Alzheimer's disease(AD). They can be visualized by thioflavin-S, silver impregnation,Congo red staining, and immunohistochemical reactions.However, that amyloid deposits generate blue autofluorescence(auto-F) has been ignored. Here, we report that visible light-induced auto-F of senile plaques(SPs) was detected and validated with conventional methods. Brain slices from APP/PS1(amyloid precursor protein/presenilin1) transgenic mice were mounted on slides, rinsed,coverslipped and observed for details of the imaging and spectral characteristics of the auto-F of SPs. Then the slices were treated with the above classic methods for comparative validation. We found that the SP auto-F was greatest under blue-violet excitation with a specific emission spectrum, and was much easier, more sensitive, and reliable than the classic methods. Because it does not damage slices, observation of auto-F can be combined with all post-staining techniques in slices and for brain-wide imaging in AD.

Long-Term Cognitive Improvement After Benfotiamine Administration in Patients with Alzheimer＇s Disease

Abstract To date, we still lack disease-modifying thera- pies for Alzheimer＇s disease （AD）. Here, we report that long-term administration of benfotiamine improved the cognitive ability of patients with AD. Five patients with mild to moderate AD received oral benfotiamine （300 mg daily） over 18 months. All patients were examined by positron emission tomography with Pittsburgh compound B （PiB-PET） and exhibited positive imaging with β- amyloid deposition, and three received PiB-PET imaging at follow-up. The five patients exhibited cognitive improve- ment as assayed by the Mini-Mental Status Examination （MMSE） with an average increase of 3.2 points at month 18 of benfotiamine administration. The three patients who received follow-up PiB-PET had a 36.7% increase in the average standardized uptake value ratio in the brain com- pared with that in the first scan. Importantly, the MMSE scores of these three had an average increase of 3 points during the same period. Benfotiamine significantly improved the cognitive abilities of mild to moderate AD patients independently of brain amyloid accumulation. Ourstudy provides new insight to the development of disease- modifying therapy.

Stepping closer to treating Alzheimer’s disease patients with BACE1 inhibitor drugs

Alzheimer’s disease(AD)is the most common age-dependent neurodegenerative disease which impairs cognitive function and gradually causes patients to be unable to lead normal daily lives.While the etiology of AD remains an enigma,excessive accumulation ofβ-amyloid peptide(Aβ)is widely believed to induce pathological changes and cause dementia in brains of AD patients.BACE1 was discovered to initiate the cleavage of amyloid precursor protein(APP)at theβ-secretase site.Only after this cleavage doesγ-secretase further cleave the BACE1-cleaved C-terminal APP fragment to release Aβ.Hence,blocking BACE1 proteolytic activity will suppress Aβgeneration.Due to the linkage of Aβto the potential cause of AD,extensive discovery and development efforts have been directed towards potent BACE1 inhibitors for AD therapy.With the recent breakthrough in developing brain-penetrable BACE1 inhibitors,targeting amyloid deposition-mediated pathology for AD therapy has now become more practical.This review will summarize various strategies that have successfully led to the discovery of BACE1 drugs,such as MK8931,AZD-3293,JNJ-54861911,E2609 and CNP520.These drugs are currently in clinical trials and their updated states will be discussed.With the promise of reducing Aβgeneration and deposition with no alarming safety concerns,the amyloid cascade hypothesis in AD therapy may finally become validated.

Role of BACE1 in Alzheimer’s synaptic function

Alzheimer’s disease(AD)is the most common age-dependent disease of dementia,and there is currently no cure available.This hallmark pathologies of AD are the presence of amyloid plaques and neurofibrillary tangles.Although the exact etiology of AD remains a mystery,studies over the past 30 have shown that abnormal generation or accumulation of β-amyloid peptides(Aβ)is likely to be a predominant early event in AD pathological development.Aβ is generated from amyloid precursor protein(APP)via proteolytic cleavage by β-site APP cleaving enzyme 1(BACE1).Chemical inhibition of BACE1 has been shown to reduce Aβ in animal studies and in human trials.While BACE1 inhibitors are currently being tested in clinical trials to treat AD patients,it is highly important to understand whether BACE1 inhibition will significantly impact cognitive functions in AD patients.This review summarizes the recent studies on BACE1 synaptic functions.This knowledge will help to guide the proper use of BACE1 inhibitors in AD therapy.

Grain-sized moxibustion inhibits the progression of Alzheimer disease in 5XFAD transgenic mice

Objective To investigate whether grain-sized moxibustion at Xinshu(BL15)and Shenshu(BL23)can alleviate cognitive decline and other pathologic features in early-stage Alzheimer disease(AD)using transgenic mice with 5 familial AD mutations(5XFAD).Methods The genotype of transgenic mice was detected by polymerase chain reaction.A total of 40 transgenic mice(1.5 months old)were randomly and equally allocated to an AD model group(5XFAD group)or a grain-sized moxibustion group(5XFAD+GM group),with 20 wild-type(WT)mice(C57BL/6J)serving as the normal control group(WT group).Mice in the 5XFAD+GM group were treated by grain-sized moxibustion at bilateral Xinshu(BL15)and Shenshu(BL23).Mice in the WT group and 5XFAD group received no treatment but were restrained to ensure exposure to a similar experimental condition.Cognitive function and memory were assessed with the Morris water maze and Y-maze tests.The amyloidβ40(Aβ40)and amyloidβ42(Aβ42)levels in the brain were evaluated by enzyme-linked immunosorbent assay;amyloid plaque deposition in brain tissue sections was detected by thioflavin-S staining;the expression of glial fibrillary acidic protein(GFAP),cluster of differentiation 11b(CD11b),brain-derived neurotrophic factor(BDNF),and choline acetyltransferase(ChAT)in the hippocampus and prefrontal cortex was analyzed by immunohistochemistry.Results In the Morris water maze test,compared with the 5XFAD group,mice in the 5XFAD+GM group had a shorter escape latency and more target area crossings and spent more time in the target quadrant(P<0.05).In the Y-maze test,compared with the 5XFAD group,the number of training times of the 5XFAD+GM group was significantly decreased(P<0.05),together with more correct responses(P<0.05).Compared with the 5XFAD group,the levels of Aβ40 and Aβ42 in the brain tissue of the 5XFAD+GM group were significantly lower(P<0.05);in the hippocampus and prefrontal cortex,the total number of amyloidβplaque deposition were significantly lower(P<0.05);the expression levels of GFAP and CD11b were significantly reduced(P<0.05);and the expression levels of ChAT and BDNF were significantly increased(P<0.05).Conclusion Grain-sized moxibustion at Xinshu(BL15)and Shenshu(BL23)greatly improves learning and memory functions,decreases the levels of Aβ40 and Aβ42,inhibits amyloidβplaque deposition,decreases the expression of GFAP and CD11b,and increases the expression of ChAT and BDNF in AD mice to inhibit the progression of AD.