Alzheimer & Parkinson

Sham surgery is often required for cell therapies adopting a randomized placebo-controlled double-blinded trial design. Using the case of dopamine neuron therapy for Parkinson's disease, we argue that alternative trial designs should be considered instead, for several reasons relating to ethics, patient burden, ease of unblinding, and cost.

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Psychedelics have traditionally been used for spiritual and recreational purposes, but recent developments in psychotherapy have highlighted their potential as therapeutic agents. These compounds, which act as potent 5-hydroxytryptamine (5HT) agonists, have been recognized for their ability to enhance neural plasticity through the activation of the serotoninergic and glutamatergic systems. However, the implications of these findings for the treatment of neurodegenerative disorders, particularly...

Amyloid-β (Aβ) oligomers are implicated in the onset of Alzheimer's disease (AD). Herein, quinoline-derived half-curcumin-dioxaborine (Q-OB) fluorescent probe was designed for detecting Aβ oligomers by finely tailoring the hydrophobicity of the biannulate donor motifs in donor-π-acceptor structure. Q-OB shows a great sensing potency in dynamically monitoring oligomerization of Aβ during amyloid fibrillogenesis in vitro. In addition, we applied this strategy to fluorometrically analyze Aβ...

Idiopathic Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, which is associated with neuroinflammation and reactive gliosis. The underlying cause of PD and the concurrent neuroinflammation are not well understood. In this study, we utilize human and murine neuronal lines, stem cell-derived dopaminergic neurons, and mice to demonstrate that three previously identified genetic risk factors for PD, namely SATB1, MIR22HG, and GBA,...

The ε4 allele of apolipoprotein E (APOE) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD). Knockdown of ε4 may provide a therapeutic strategy for AD, but the effect of APOE loss of function (LoF) on AD pathogenesis is unknown. We searched for APOE LoF variants in a large cohort of controls and patients with AD and identified seven heterozygote carriers of APOE LoF variants. Five carriers were controls (aged 71-90 years), one carrier was affected by progressive...

Protein misfolding can generate toxic intermediates, which underlies several devastating diseases, such as Alzheimer's disease (AD). The surface of AD-associated amyloid-β peptide (Aβ) fibrils has been suggested to act as a catalyzer for self-replication and generation of potentially toxic species. Specifically tailored molecular chaperones, such as the BRICHOS protein domain, were shown to bind to amyloid fibrils and break this autocatalytic cycle. Here, we identify a site on the Aβ42 fibril...

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Microglia actively monitor the neighboring brain microenvironments and constantly contact synapses with their unique ramified processes. In neurodegenerative diseases, including Alzheimer's disease (AD), microglia undergo morphological and functional alterations. Whether the direct manipulation of microglia can selectively or concurrently modulate synaptic function and the response to disease-associated factors remains elusive. Here, we employ optogenetic methods to stimulate microglia in vitro...

Parkinson's disease (PD) is a progressive neurodegenerative disorder that deals with dopaminergic deficiency in Substantia nigra pars compact (SNpc) region of the brain. Dopaminergic deficiency manifests into motor dysfunction. Alpha-synuclein protein aggregation is the source for inception of the pathology. Motor symptoms include rigidity, akinesia, tremor and gait dysfunction. Pre-motor symptoms are also seen in early stage of the disease; however, they are not distinguishable. Lack of early...

Alzheimer's disease (AD) is a major global health problem today and is the most common form of dementia. AD is characterized by the formation of β-amyloid (Aβ) plaques and neurofibrillary clusters, leading to decreased brain acetylcholine levels in the brain. Another mechanism underlying the pathogenesis of AD is the abnormal phosphorylation of tau protein that accumulates at the level of neurofibrillary aggregates, and the areas most affected by this pathological process are usually the...

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Reactive astrogliosis is a common pathological hallmark of CNS injury, infection, and neurodegeneration, where reactive astrocytes can be protective or detrimental to normal brain functions. Currently, the mechanisms regulating neuroprotective astrocytes and the extent of neuroprotection are poorly understood. Here, we report that conditional deletion of serum response factor (SRF) in adult astrocytes causes reactive-like hypertrophic astrocytes throughout the mouse brain. These Srf^(GFAP-ER)CKO...

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Alzheimer's disease (AD) is characterized pathologically by amyloid-beta (Aβ) deposition in brain parenchyma and blood vessels (as cerebral amyloid angiopathy (CAA)) and by neurofibrillary tangles of hyperphosphorylated tau. Compelling genetic and biomarker evidence supports Aβ as the root cause of AD. We previously reported human transmission of Aβ pathology and CAA in relatively young adults who had died of iatrogenic Creutzfeldt-Jakob disease (iCJD) after childhood treatment with...

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In contrast to prevalent strategies which make use of β-sheet mimetics to block Aβ fibrillar growth, in this study, we designed a series of sulfonyl-γ-AApeptide helices that targeted the crucial α-helix domain of Aβ13-26 and stabilized Aβ conformation to avoid forming the neurotoxic Aβ oligomeric β-sheets. Biophysical assays such as amyloid kinetics and TEM demonstrated that the Aβ oligomerization and fibrillation could be greatly prevented and even reversed in the presence of...

Increasing evidence supports a role for deficient Wnt signaling in Alzheimer's disease (AD). Studies reveal that the secreted Wnt antagonist Dickkopf-3 (DKK3) colocalizes to amyloid plaques in AD patients. Here, we investigate the contribution of DKK3 to synapse integrity in healthy and AD brains. Our findings show that DKK3 expression is upregulated in the brains of AD subjects and that DKK3 protein levels increase at early stages in the disease. In hAPP-J20 and hAPP^(NL-G-F/NL-G-F) mouse AD...

Parkinson's Disease's (PD) neuropsychological profile is often characterized by altered performance in executive functions (EF) tasks, with a remarkable impact on patients' quality of life. To date, the available neuroimaging literature lacks conclusive evidence about neural patterns underlying EF deficits in PD. Here, we aimed to synthesize the results of PET/fMRI studies examining the differences in brain activation between PD patients and controls during EF tasks, focusing on the three main...