Emotion influences various cognitive processes, including learning and memory. The amygdala is specialized for input and processing of emotion, while the hippocampus is essential for declarative or ...episodic memory. During emotional reactions, these two brain regions interact to translate the emotion into particular outcomes. Here, we briefly introduce the anatomy and functions of amygdala and hippocampus, and then present behavioral, electrophysiological, optogenetic and biochemical evidence from recent studies to illustrate how amygdala and hippocampus work synergistically to form long-term memory. With recent technological advances, the causal investigations of specific neural circuit between amygdala and hippocampus will help us understand the brain mechanisms of emotion-regulated memories and improve clinical treatment of emotion-associated memory disorders in patients.
The basolateral amygdala (BLA) and ventral hippocampal CA1 (vCA1) are cellularly and functionally diverse along their anterior-posterior and superficial-deep axes. Here, we find that anterior BLA ...(aBLA) and posterior BLA (pBLA) innervate deep-layer calbindin1-negative (Calb1-) and superficial-layer calbindin1-positive neurons (Calb1+) in vCA1, respectively. Photostimulation of pBLA-vCA1 inputs has an anxiolytic effect in mice, promoting approach behaviours during conflict exploratory tasks. By contrast, stimulating aBLA-vCA1 inputs induces anxiety-like behaviour resulting in fewer approaches. During conflict stages of the elevated plus maze task vCA1
neurons are preferentially activated at the open-to-closed arm transition, and photostimulation of vCA1
neurons at decision-making zones promotes approach with fewer retreats. In the APP/PS1 mouse model of Alzheimer's disease, which shows anxiety-like behaviour, photostimulating the pBLA-vCA1
circuit ameliorates the anxiety in a Calb1-dependent manner. These findings suggest the pBLA-vCA1
circuit from heterogeneous BLA-vCA1 connections drives approach behaviour to reduce anxiety-like behaviour.
Morphing materials have promising applications in various fields, yet how to program the self‐shaping process for specific configurations remains a challenge. Herein we show a versatile approach to ...control the buckling of individual domains and thus the outcome configurations of planar‐patterned hydrogels. By photolithography, high‐swelling disc gels were positioned in a non‐swelling gel sheet; the swelling mismatch resulted in out‐of‐plain buckling of the disc gels. To locally control the buckling direction, masks with holes were used to guide site‐specific swelling of the high‐swelling gel under the holes, which built a transient through‐thickness gradient and thus directed the buckling during the subsequent unmasked swelling process. Therefore, various configurations of an identical patterned hydrogel can be programmed by the pre‐swelling step with different masks to encode the buckling directions of separate domains.
A swell idea: Morphing structures of photo‐lithographically patterned hydrogels were programmed by selective pre‐swelling of the regions with a high‐swelling capacity. This step built a transient through‐thickness gradient and directed the buckling direction. Different combinations of localized buckling led to different morphing structures from identically patterned hydrogels.
Memory loss is the most common clinical sign in Alzheimer's disease (AD); thus, searching for peripheral biomarkers to predict cognitive decline is promising for early diagnosis of AD. As platelets ...share similarities to neuron biology, it may serve as a peripheral matrix for biomarkers of neurological disorders. Here, we conducted a comprehensive and in‐depth platelet proteomic analysis using TMT‐LC‐MS/MS in the populations with mild cognitive impairment (MCI, MMSE = 18–23), severe cognitive impairments (AD, MMSE = 2–17), and the age‐/sex‐matched normal cognition controls (MMSE = 29–30). A total of 360 differential proteins were detected in MCI and AD patients compared with the controls. These differential proteins were involved in multiple KEGG pathways, including AD, AMP‐activated protein kinase (AMPK) pathway, telomerase RNA localization, platelet activation, and complement activation. By correlation analysis with MMSE score, three positively correlated pathways and two negatively correlated pathways were identified to be closely related to cognitive decline in MCI and AD patients. Partial least squares discriminant analysis (PLS‐DA) showed that changes of nine proteins, including PHB, UQCRH, CD63, GP1BA, FINC, RAP1A, ITPR1/2, and ADAM10 could effectively distinguish the cognitively impaired patients from the controls. Further machine learning analysis revealed that a combination of four decreased platelet proteins, that is, PHB, UQCRH, GP1BA, and FINC, was most promising for predicting cognitive decline in MCI and AD patients. Taken together, our data provide a set of platelet biomarkers for predicting cognitive decline which may be applied for the early screening of AD.
Deep profiling of platelet proteome in healthy aging subjects and MCI/AD cases. Some individual candidate biomarkers in platelets closely reflect the pathophysiological process of AD. The identified novel platelet combination biomarkers can distinguish healthy aging subjects and cognitively impaired subjects.
Microtubule associated protein tau is a phosphoprotein which potentially has 80 serine/threonine and 5 tyrosine phosphorylation sites. Normal brain tau contains 2-3 moles of phosphate per mole of the ...protein. In Alzheimer's disease brain, tau is abnormally hyperphosphorylated to a stoichiometry of at least three-fold greater than normal tau, and in this altered state it is aggregated into paired helical filaments forming neurofibrillary tangles, a histopathological hallmark of the disease. The abnormal hyperphosphorylation of tau is also a hallmark of several other related neurodegenerative disorders, called tauopathies. The density of neurofibrillary tangles in the neocortex correlates with dementia and, hence, is a rational therapeutic target and an area of increasing research interest. Development of rational tau-based therapeutic drugs requires understanding of the role of various phosphorylation sites, protein kinases and phosphatases, and post-translational modifications that regulate the phosphorylation of this protein at various sites, as well as the molecular mechanism by which the abnormally hyperphosphorylated tau leads to neurodegeneration and dementia. In this article we briefly review the progress made in these areas of research.
As a principal neuronal microtubule-associated protein, tau has been recognized to play major roles in promoting microtubule assembly and stabilizing the microtubules and to maintain the normal ...morphology of the neurons. Recent studies suggest that tau, upon alternative mRNA splicing and multiple posttranslational modifications, may participate in the regulations of intracellular signal transduction, development and viability of the neurons. Furthermore, tau gene mutations, aberrant mRNA splicing and abnormal posttranslational modifications, such as hyperphosphorylation, have also been found in a number of neurodegenerative disorders, collectively known as tauopathies. Therefore, changes in expression of the tau gene, alternative splicing of its mRNA and its posttranslational modification can modulate the normal architecture and functions of neurons as well as in a situation of tauopathies, such as Alzheimer's disease. The primary aim of this review is to summarize the latest developments and perspectives in our understanding about the roles of tau, especially hyperphosphorylation, in the development, degeneration and protection of neurons.
Microtubule associated protein (MAP) tau is abnormally hyperphosphorylated in Alzheimer's disease (AD) and related tauopathies; in this form it is the major protein subunit of paired helical ...filaments (PHF)/neurofibrillary tangles. However, the nature of protein kinases and phosphatases and tau sites involved in this lesion has been elusive. We investigated self‐assembly and microtubule assembly promoting activities of hyperphosphorylated tau isolated from Alzheimer disease brain cytosol, the AD abnormally hyperphosphorylated tau (AD P‐tau) before and after dephosphorylation by phosphoseryl/phosphothreonyl protein phosphatase‐2A (PP‐2A), and then rephosphorylation by cyclic AMP‐dependent protein kinase (PKA), calcium, calmodulin‐dependent protein kinase II (CaMKII), glycogen synthase kinase‐3β (GSK‐3β) and cyclin‐dependent protein kinase 5 (cdk5) in different kinase combinations. We found that (i) dephosphorylation of AD P‐tau by PP‐2A inhibits its polymerization into PHF/straight filaments (SF) and restores its binding and ability to promote assembly of tubulin into microtubules; (ii) rephosphorylation of PP‐2A‐dephosphorylated AD P‐tau by sequential phosphorylation by PKA, CaMKII and GSK‐3β or cdk5, and as well as by cdk5 and GSK‐3β, promotes its self‐assembly into tangles of PHF similar to those seen in Alzheimer brain, and (iii) phosphorylation of tau sites required for this pathology are Thr231 and Ser262, along with several sites flanking the microtubule binding repeat region. Phosphorylation of recombinant human brain tau441 yielded similar results as the PP‐2A dephosphorylated AD P‐tau, except that mostly SF were formed. The conditions for the abnormal hyperphosphorylation of tau that promoted its self‐assembly also induced the microtubule assembly inhibitory activity. These findings suggest that activation of PP‐2A or inhibition of either both GSK‐3β and cdk5 or one of these two kinases plus PKA or CaMKII might be required to inhibit Alzheimer neurofibrillary degeneration.
Intracellular accumulation of tau is a hallmark pathology in Alzheimer disease (AD) and the related tauopathies, thus targeting tau could be promising for drug development. Proteolysis Targeting ...Chimera (PROTAC) is a novel drug discovery strategy for selective protein degradation from within cells.
A novel small-molecule PROTAC, named as C004019 with a molecular mass of 1,035.29 dalton, was designed to simultaneously recruite tau and E3-ligase (Vhl) and thus to selectively enhance ubiquitination and proteolysis of tau proteins. Western blotting, immunofluoresence and immunohistochemical staining were employed to verify the effects of C004019 in cell models (HEK293 and SH-SY5Y) and mouse models (hTau-transgenic and 3xTg-AD), respectively. The cognitive capacity of the mice was assessed by a suite of behavior experiments. Electrophysiology and Golgi staining were used to evaluate the synaptic plasticity.
C004019 induced a robust tau clearance
promoting its ubiquitination-proteasome-dependent proteolysis in HEK293 cells with stable or transient overexpression of human tau (hTau), and in SH-SY5Y that constitutively overexpress hTau. Furthermore, intracerebral ventricular infusion of C004019 induced a robust tau clearance
. Most importantly, both single-dose and multiple-doses (once per 6 days for a total 5 times) subcutaneous administration of C004019 remarkably decreased tau levels in the brains of wild-type, hTau-transgenic and 3xTg-AD mice with improvement of synaptic and cognitive functions.
The PROTAC (C004019) created in the current study can selectively and efficiently promote tau clearance both
and
, which provides a promising drug candidate for AD and the related tauopathies.
BDNF/TrkB neurotrophic signaling regulates neuronal development, differentiation, and survival, and deficient BDNF/TrkB activity underlies neurodegeneration in Alzheimer’s disease (AD). However, ...exactly how BDNF/TrkB participates in AD pathology remains unclear. Here, we show that deprivation of BDNF/TrkB increases inflammatory cytokines and activates the JAK2/STAT3 pathway, resulting in the upregulation of transcription factor C/EBPβ. This, in turn, results in increased expression of δ-secretase, leading to both APP and Tau fragmentation by δ-secretase and neuronal loss, which can be blocked by expression of STAT3 Y705F, knockdown of C/EBPβ, or the δ-secretase enzymatic-dead C189S mutant. Inhibition of this pathological cascade can also rescue impaired synaptic plasticity and cognitive dysfunctions. Importantly, reduction in BDNF/TrkB neurotrophic signaling is inversely coupled with an increase in JAK2/STAT3, C/EBPβ, and δ-secretase escalation in human AD brains. Therefore, our findings provide a mechanistic link between BDNF/TrkB reduction, C/EBPβ upregulation, δ-secretase activity, and Aβ and Tau alterations in murine brains.
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•Deprivation of BDNF increases inflammatory cytokines•Deprivation of BDNF upregulates C/EBPβ by JAK2/STAT3 pathway•BDNF knockout increases expression of AEP by C/EBPβ•Inhibition of JAK2/STAT3/C/EBPβ/AEP prevents BDNF-depletion-mediated pathology
Deficient BDNF/TrkB activity underlies AD pathogenesis. Wang et al. report that deprivation of BDNF/TrkB increases inflammatory cytokines and activates the JAK2/STAT3 pathway, resulting in the upregulation of C/EBPβ/AEP signaling. Reduction of BDNF is inversely coupled with the aforementioned pathway in AD brains. Inhibition of JAK2/STAT3/C/EBPβ/AEP prevents BDNF-depletion-mediated pathology.
Phospho-tau accumulation and adult hippocampal neurogenesis (AHN) impairment both contribute importantly to the cognitive decline in Alzheimer’s disease (AD), but whether and how tau dysregulates AHN ...in AD remain poorly understood. Here, we found a prominent accumulation of phosphorylated tau in GABAergic interneurons in the dentate gyrus (DG) of AD patients and mice. Specific overexpression of human tau (hTau) in mice DG interneurons induced AHN deficits but increased neural stem cell-derived astrogliosis, associating with a downregulation of GABA and hyperactivation of neighboring excitatory neurons. Chemogenetic inhibition of excitatory neurons or pharmacologically strengthening GABAergic tempos rescued the tau-induced AHN deficits and improved contextual cognition. These findings evidenced that intracellular accumulation of tau in GABAergic interneurons impairs AHN by suppressing GABAergic transmission and disinhibiting neural circuits within the neurogenic niche, suggesting a potential of GABAergic potentiators for pro-neurogenic or cell therapies of AD.
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•Phospho-tau is accumulated in DG GABAergic interneurons of AD patients and mice•Interneuron overexpressing human tau impairs adult hippocampal neurogenesis•Tau accumulation reduces GABA, disinhibits local circuits, and promotes astrogliosis•THIP, a δ-GABAAR agonist, improves neurogenesis and cognition in AD mice
Impaired adult hippocampal neurogenesis contributes to the cognitive decline in Alzheimer’s disease. Zheng et al. report that phospho-tau accumulation in dentate gyrus GABAergic interneurons disrupts adult hippocampal neurogenesis and increased astrogliosis. Importantly, strengthening GABAergic signaling can rescue neurogenesis and improve cognitive functions in mouse models of Alzheimer’s disease.
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