Phytomedicines as potential inhibitors of β amyloid aggregation: significance to Alzheimer's disease

Throughout the history of drug development, plants have been an important source for the discovery of novel therapeutically active compounds for many diseases. The ethnopharmacological approach has provided several leads to identify potential new drugs from plant sources, including those for memory disorders. For the treatment of Alzheimer's disease the drug discovery focus shifted from cholinesterase inhibitors, to other targets primarily based on two key neuropathological hallmarks, namely the hyperphosphorylation of the tau protein resulting in the formation of neurofibrillary tangles(NFTs), and the increased formation and aggregation of amyloid-beta peptide(Aβ) derived from amyloid precursor protein(APP). The present article aims to provide a comprehensive literature survey of plants and their constituents that have been tested for Aβ aggregation, thus possibly relieving several features of Alzheimer's disease(AD).

Amyloid cross-seeding between Ab and hIAPP in relation to the pathogenesis of Alzheimer and type 2 diabetes

Amyloid cross-seeding of different amyloid proteins is considered as a highly possible mechanism for exacerbating the transmissible pathogenesis of protein misfolding disease(PMDs)and for explaining a molecular link between different PMDs,including Alzheimer disease(AD)and type 2 diabetes(T2D),AD and Parkinson disease(PD),and AD and prion disease.Among them,AD and T2D are the most prevalent PMDs,affecting millions of people globally,while Ab and hIAPP are the causative peptides responsible for AD and T2D,respectively.Increasing clinical and epidemiological evidences lead to a hypothesis that the cross-seeding of Ab and hIAPP is more biologically responsible for a pathological link between AD and T2D.In this review,we particularly focus on(i)the most recent and important findings of amyloid cross-seeding between Ab and hIAPP from in vitro,in vivo,and in silico studies,(ii)a mechanistic role of structural compatibility and sequence similarity of amyloid proteins(beyond Ab and hIAPP)in amyloid cross-seeding,and(iii)several current challenges and future research directions in this lessstudied field.Review of amyloid cross-seeding hopefully provides some mechanistic understanding of amyloidogenesis and inspires more efforts for the better design of next-generation drugs/strategies to treat different PMDs simultaneously.

Optimal Formula of Angelica sinensis Ameliorates Memory Deficits in β-amyloid Protein-induced Alzheimer's Disease Rat Model

Objective:Angelica(A.)sinensis is used as a traditional medical herb for the treatment of neurodegeneration,aging,and inflammation in Asia.A.sinensis optimal formula(AOF)is the best combination in A.sinensis that has been screened to rescue the cognitive ability in P-amyloid peptide(Ap25-35)-treated Alzheimer’s disease(AD)rats.The objective of this study was to investigate the effect of AOF on the learning and memory of AD rats as well as to explore the underlying mechanisms.

α-Synuclein oligomers and fibrils:partners in crime in synucleinopathies

The misfolding and aggregation of a-synuclein is the general hallmark of a group of devastating neurodegenerative pathologies referred to as synucleinopathies,such as Parkinson’s disease,dementia with Lewy bodies,and multiple system atrophy.In such conditions,a range of different misfolded aggregates,including oligomers,protofibrils,and fibrils,are present both in neurons and glial cells.Growing expe rimental evidence supports the proposition that solu ble oligomeric assemblies,formed during the early phases of the aggregation process,are the major culprits of neuronal toxicity;at the same time,fibrillar confo rmers appear to be the most efficient at propagating among interconnected neurons,thus contributing to the spreading ofα-synuclein pathology.Moreover,α-synuclein fibrils have been recently repo rted to release soluble and highly toxic oligomeric species,responsible for an immediate dysfunction in the recipient neurons.In this review,we discuss the current knowledge about the plethora of mechanisms of cellular dysfunction caused byα-synuclein oligome rs and fibrils,both contributing to neurodegeneration in synucleinopathies.

Aβ-Aggregation-Generated Blue Autofluorescence Illuminates Senile Plaques as well as Complex Blood and Vascular Pathologies in Alzheimer’s Disease

Senile plaque blue autofluorescence was discovered around 40 years ago,however,its impact on Alzheimer’s disease(AD)pathology has not been fully examined.We analyzed senile plaques with immunohistochemistry and fluorescence imaging on AD brain sections and also Aβ aggregation in vitro.In DAPI or Hoechst staining,the nuclear blue fluorescence could only be correctly assigned after subtracting the blue plaque autofluorescence.The flower-like structures wrapping dense-core blue fluorescence formed by cathepsin D staining could not be considered central-nucleated neurons with defective lysosomes since there was no nuclear staining in the plaque core when the blue autofluorescence was subtracted.Both Aβ self-oligomers and Aβ/hemoglobin heterocomplexes generated blue autofluorescence.The Aβ amyloid blue autofluorescence not only labels senile plaques but also illustrates red cell aggregation,hemolysis,cerebral amyloid angiopathy,vascular plaques,vascular adhesions,and microaneurysms.In summary,we conclude that Aβ-aggregation-generated blue autofluorescence is an excellent multi-amyloidosis marker in Alzheimer’s disease.

Targeting amyloid proteins for clinical diagnosis of neurodegenerative diseases

Abnormal aggregation and accumulation of pathological amyloid proteins such as amyloid-β,Tau,and𝛼α-synuclein play key pathological roles and serve as histological hallmarks in different neurodegenerative diseases(NDs)such as Alzheimer’s disease(AD)and Parkinson’s disease(PD).In addition,various post-translational modifications(PTMs)have been identified on pathological amyloid proteins and are subjected to change during disease progression.Given the central role of amyloid proteins in NDs,tremendous efforts have been made to develop amyloid-targeting strategies for clinical diagnosis and molecular classification of NDs.In this review,we summarize two major strategies for targeting amyloid aggregates,with a focus on the trials in AD diagnosis.The first strategy is a positron emission tomography(PET)scan of protein aggregation in the brain.We mainly focus on introducing the development of small-molecule PET tracers for specifically recognizing pathological amyloid fibrils.The second strategy is the detection of PTM biomarkers on amyloid proteins in cerebrospinal fluid and plasma.We discuss the pathological roles of different PTMs in diseases and how we can use the PTM profile of amyloid proteins for clinical diagnosis.Finally,we point out the potential technical challenges of these two strategies,and outline other potential strategies,as well as a combination of multiple strategies,for molecular diagnosis of NDs.

Reactive oxidative species enhance amyloid toxicity in APP/PS1 mouse neurons

Objective To investigate whether intracellular amyloid β （iAβ） induces toxicity in wild type （WT） and APP/PS1 mice, a mouse model of Alzheimer＇s disease. Methods Different forms of Aβ aggregates were microinjected into cultured WT or APP/PS1 mouse hippocampal neurons. TUNEL staining was performed to examine neuronal cell death. Reactive oxidative species （ROS） were measured by MitoSOXTM Red mitochondrial superoxide indicator. Results Crude, monomer and protofibrilAβ induced more toxicity inAPP/PS1 neurons than in WT neurons. ROS are involved in mediating the vulnerability of APP/PS1 neurons to iAβ toxicity. Conclusion Oxidative stress may mediate cell death induced by iAβ in neurons.