Explore the vast range of titles available.

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disease characterized by the accumulation of cholestanol. CTX patients often suffer from cognitive impairment. We found that serum cholestanol levels are higher in Alzheimer’s disease (AD) patients than in control subjects. Thus, we tested whether cholestanol regulates the pathogenesis of AD. Cholestanol promotes tau fragmentation and hyperphosphorylation by activating asparagine endopeptidase (AEP). AEP knockdown alleviates cholestanol-induced tau fragmentation and phosphorylation. Feeding cholestanol to tau P301S mice aggravates tau pathology and behavioral defects, while knockout of AEP ameliorates cholestanol-induced tau pathology and behavioral defects in tau P301S mice. These results highlight the role of AEP-mediated tau cleavage in cholestanol-induced tau pathology and cognitive decline. The data also identify the potential therapeutic target of AEP in AD, particularly in AD patients with elevated serum cholestanol levels.

The pathological hallmarks of Parkinson's disease (PD) are the progressive loss of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies (LBs) in remaining neurons. LBs primarily consist of aggregated α-Synuclein (α-Syn). However, accumulating evidence suggests that Tau, which is associated with tauopathies such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and argyrophilic grain disease, is also involved in the pathophysiology of PD. A genome-wide association study (GWAS) identified MAPT, the gene encoding the Tau protein, as a risk gene for PD. Autopsy of PD patients also revealed the colocalization of Tau and α-Syn in LBs. Experimental evidence has shown that Tau interacts with α-Syn and influences the pathology of α-Syn in PD. In this review, we discuss the structure and function of Tau and provide a summary of the current evidence supporting Tau’s involvement as either an active or passive element in the pathophysiology of PD, which may provide novel targets for the early diagnosis and treatment of PD.

Cholesterol is an indispensable component of the cell membrane and plays vital roles in critical physiological processes. Brain cholesterol accounts for a large portion of total cholesterol in the human body, and its content must be tightly regulated to ensure normal brain function. Disorders of cholesterol metabolism in the brain are linked to neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and other atypical cognitive deficits that arise at old age. However, the specific role of cholesterol metabolism disorder in the pathogenesis of neurodegenerative diseases has not been fully elucidated. Statins that are a class of lipid-lowering drugs have been reported to have a positive effect on neurodegenerative diseases. Herein, we reviewed the physiological and pathological conditions of cholesterol metabolism and discussed the possible mechanisms of cholesterol metabolism and statin therapy in neurodegenerative diseases.

The noradrenergic locus ceruleus (LC) is the first site of detectable tau pathology in Alzheimer’s disease (AD), but the mechanisms underlying the selective vulnerability of the LC in AD have not been completely identified. In the present study, we show that DOPEGAL, a monoamine oxidase A (MAO-A) metabolite of norepinephrine (NE), reacts directly with the primary amine on the Lys353 residue of tau to stimulate its aggregation and facilitate its propagation. Inhibition of MAO-A or mutation of the Lys353 residue to arginine (Lys353Arg) decreases tau Lys353–DOPEGAL levels and diminishes tau pathology spreading. Wild-type tau preformed fibrils (PFFs) trigger Lys353–DOPEGAL formation, tau pathology propagation and cognitive impairment in MAPT transgenic mice, all of which are attenuated with PFFs made from the Lys353Arg mutant. Thus, the selective vulnerability of LC neurons in AD may be explained, in part, by NE oxidation via MAO-A into DOPEGAL, which covalently modifies tau and accelerates its aggregation, toxicity and propagation. DOPEGAL, a metabolite of norepinephrine in the locus ceruleus, covalently modifies tau and accelerates its aggregation and propagation, leading to cognitive deficits in Alzheimer’s disease.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein that is predominantly expressed by microglia in the brain. The proteolytic shedding of TREM2 results in the release of soluble TREM2 (sTREM2), which is increased in the cerebrospinal fluid of patients with Alzheimer’s disease (AD). It remains unknown whether sTREM2 regulates the pathogenesis of AD. Here we identified transgelin-2 (TG2) expressed on neurons as the receptor for sTREM2. The microglia-derived sTREM2 binds to TG2, induces RhoA phosphorylation at S188, and deactivates the RhoA-ROCK-GSK3β pathway, ameliorating tau phosphorylation. The sTREM2 (77-89) fragment, which is the minimal active sequence of sTREM2 to activate TG2, mimics the inhibitory effect of sTREM2 on tau phosphorylation. Overexpression of sTREM2 or administration of the active peptide rescues tau pathology and behavioral defects in the tau P301S transgenic mice. Together, these findings demonstrate that the sTREM2-TG2 interaction mediates the cross-talk between microglia and neurons. sTREM2 and its active peptide may be a potential therapeutic intervention for tauopathies including AD. In this study, the authors found that sTREM2 attenuates tau hyperphosphorylation by activating transgelin-2. They developed an active peptide that mimics the protective effect of sTREM2, which may be an innovative therapeutic intervention for AD.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a receptor mainly expressed on the surface of microglia. It mediates multiple pathophysiological processes in various diseases. Recently, TREM2 has been found to play a role in the development of Alzheimer’s disease (AD). TREM2 is a transmembrane protein that is specifically expressed on microglia in the brain. It contains a long ectodomain that directly interacts with the extracellular environment to regulate microglial function. The ectodomain of TREM2 is processed by a disintegrin and metalloprotease, resulting in the release of a soluble form of TREM2 (sTREM2). Recent studies have demonstrated that sTREM2 is a bioactive molecule capable of binding ligands, activating microglia, and regulating immune responses during the AD continuum. Clinical studies revealed that sTREM2 level is elevated in cerebrospinal fluid (CSF) of AD patients, and the sTREM2 level is positively correlated with the levels of classical CSF biomarkers, namely t-tau and p-tau, indicating that it is a reliable predictor of the early stages of AD. Herein, we summarize the key results on the generation, structure, and function of sTREM2 to provide new insights into TREM2-related mechanisms underlying AD pathogenesis and to promote the development of TREM2-based therapeutic strategy.

Alzheimer's disease (AD) is characterized by the development of amyloid plaques and neurofibrillary tangles (NFTs) consisting of aggregated β-amyloid (Aβ) and tau, respectively. The amyloid hypothesis has been the predominant framework for research in AD for over two decades. According to this hypothesis, the accumulation of Aβ in the brain is the primary factor initiating the pathogenesis of AD. However, it remains elusive what factors initiate Aβ aggregation. Studies demonstrate that AD has multiple causes, including genetic and environmental factors. Furthermore, genetic factors, many age-related events and pathological conditions such as diabetes, traumatic brain injury (TBI) and aberrant microbiota also affect the aggregation of Aβ. Here we provide an overview of the age-related early events and other pathological processes that precede Aβ aggregation.

Neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, are characterized by the aggregation of misfolded proteins, including Aβ, tau and α-synuclein. It is well recognized that these misfolded proteins are able to self-propagate and spread throughout the nervous system and cause neuronal injury in a way that resembles prion disease. These disease-specific misfolded proteins demonstrate unique features, including the seeding barrier, the conformational memory effect, strain selection and strain evolution, based on the presence of various strains. However, the accurate definition of the term strain remains to be clarified. Here, a clear interpretation is proposed by a retrospective of its history in prion research and the recent progress in neurodegeneration research. Furthermore, the causes contributing to the genesis of various strains are also summarized. Deeper insight into strains helps us to understand the phenomena we observe in this field and it also enlightens us on the elusive mechanisms and management of neurodegeneration.

Background The pathologic accumulation and aggregation of tau is a hallmark of tauopathies including Alzheimer’s disease (AD). However, the molecular mechanisms mediating tau aggregation in AD remain elusive. The incidence of AD is increased in patients with type 2 diabetes (T2DM), which is characterized by the amyloid deposition of islet amyloid polypeptide (IAPP) in the pancreas. However, the molecular mechanisms bridging AD and T2DM remain unknown. Methods We first examined the presence of IAPP in the neurofibrillary tangles of AD patients. Then we tested the effect of IAPP on tau aggregation. The biochemical and biological characteristics of the IAPP-tau fibrils were tested in vitro. The seeding activity and neurotoxicity of the IAPP-tau fibrils were confirmed in cultured neurons. Lastly, the effect of IAPP on tau pathology and cognitive impairments was determined by injecting the IAPP-tau fibrils and IAPP fibrils into the hippocampus of tau P301S mice. Results We found that IAPP interacts with tau and accelerates the formation of a more toxic strain, which shows distinct morphology with enhanced seeding activity and neurotoxicity in vitro. Intrahippocampal injection of the IAPP-tau strain into the tau P301S transgenic mice substantially promoted the spreading of tau pathology and induced more severe synapse loss and cognitive deficits, when compared with tau fibrils. Furthermore, intracerebral injection of synthetic IAPP fibrils initiated tauopathy in the brain of tau P301S transgenic mice. Conclusions These observations indicate that IAPP acts as a crucial mediator of tau pathology in AD, and provide a mechanistic explanation for the higher risk of AD in individuals with T2DM.

Parkinson’s disease (PD) is a neurodegenerative disease characterized by the death of dopaminergic neurons in the substantia nigra and the formation of Lewy bodies that are composed of aggregated α-synuclein (α-Syn). However, the factors that regulate α-Syn pathology and nigrostriatal dopaminergic degeneration remain poorly understood. Previous studies demonstrate cholesterol 24-hydroxylase (CYP46A1) increases the risk for PD. Moreover, 24-hydroxycholesterol (24-OHC), a brain-specific oxysterol that is catalyzed by CYP46A1, is elevated in the cerebrospinal fluid of PD patients. Herein, we show that the levels of CYP46A1 and 24-OHC are elevated in PD patients and increase with age in a mouse model. Overexpression of CYP46A1 intensifies α-Syn pathology, whereas genetic removal of CYP46A1 attenuates α-Syn neurotoxicity and nigrostriatal dopaminergic degeneration in the brain. Moreover, supplementation with exogenous 24-OHC exacerbates the mitochondrial dysfunction induced by α-Syn fibrils. Intracerebral injection of 24-OHC enhances the spread of α-Syn pathology and dopaminergic neurodegeneration via elevated X-box binding protein 1 (XBP1) and lymphocyte-activation gene 3 (LAG3) levels. Thus, elevated CYP46A1 and 24-OHC promote neurotoxicity and the spread of α-Syn via the XBP1–LAG3 axis. Strategies aimed at inhibiting the CYP46A1-24-OHC axis and LAG3 could hold promise as disease-modifying therapies for PD.