Tau in Alzheimer’s Disease:Pathological Alterations and an Attractive Therapeutic Target

Alzheimer’s disease(AD)is an age-related neurodegenerative disease with two major hallmarks:extracellular amyloid plaques made of amyloid-β(Aβ)and intracellular neurofibrillary tangles(NFTs)of abnormally hyperphosphorylated tau.The number of NFTs correlates positively with the severity of dementia in AD patients.However,there is still no efficient therapy available for AD treatment and prevention so far.A deeper understanding of AD pathogenesis has identified novel strategies for the generation of specific therapies over the past few decades.Several studies have suggested that the prion-like seeding and spreading of tau pathology in the brain may be a key driver of AD.Tau protein is considered as a promising candidate target for the development of therapeutic interventions due to its considerable pathological role in a variety of neurodegenerative disorders.Abnormal tau hyperphosphorylation plays a detrimental pathological role,eventually leading to neurodegeneration.In the present review,we describe the recent research progresses in the pathological mechanisms of tau protein in AD and briefly discuss tau-based therapeutic strategies.

Regulation of Social Memory by Lateral Entorhinal Cortical Projection to Dorsal Hippocampal CA2

Dear Editor,TSocial recognition memory is essential for proper conspecific interactions and its impairments are closely associated with many brain disorders,including autism,schizophrenia,and Alzheimer's disease[1-3].However,the mechanisms and neural circuits underlying social memory formation and retrieval are still unclear.Recent studies have revealed that several brain regions are involved in social memory formation,and the hippocampal dorsal CA2(dCA2)subregion appears to be its core locus[4,5].

Proteolytic cleavage is required for functional neuroligin 2 maturation and trafficking in Drosophila

Neuroligins （Nlgs） are transmembrane cell adhesion molecules playing essential roles in synapse development and function. Genetic mutations in neuroUgin genes have been linked with some neurodevelopmental disorders such as autism. These mutated Nlgs are mostly retained in the endoplasmic reticulum （ER）. However, the mechanisms underlying normal Nlg maturation and trafficking have remained largely unknown. Here, we found that Drosophila neuroligin 2 （DNlg2） undergoes proteolytic cleavage in the ER in a variety of Drosophila tissues throughout developmental stages. A region encompassing Y642-T698 is required for this process. The immature non-cleavable DNtg2 is retained in the ER and non-functionaL The C-terminal fragment of DNlg2 instead of the full-length or non-cleavable DNIg2 is able to rescue neuromuscular junction defects and GluRIIB reduction induced by dnlg2 deletion. Intriguingly, the autism-associated R598C mutation in DNIg2 leads to similar marked defects in DNIg2 proteo- lytic process and ER export, revealing a potential role of the improper Nlg cleavage in autism pathogenesis. Collectively, our find- ings uncover a specific mechanism that controls DNIg2 maturation and trafficking via proteolytic cleavage in the ER, suggesting that the perturbed proteolytic cleavage of Nlgs likely contributes to autism disorder.