Alzheimer & Parkinson

In this issue, Chadarevian et al. showed that engraftment of human iPSC-derived microglia (iMG) engineered to express secreted neprilysin (sNEP) under the plaque-responsive CD9 promoter reduces amyloid burden, neuronal damage, and inflammation in an Alzheimer's disease (AD) mouse model.¹ These findings establish a cell-based strategy to treat neurological diseases.

Parkinson's disease (PD), characterized by the selective loss of midbrain dopaminergic neurons (mDANs), is a promising target for cell replacement therapy. Two recent clinical trials¹^(,)² published in Nature report the safety and potential efficacy of human pluripotent stem cell-based approaches, representing a major milestone in regenerative medicine for PD.

N⁶-methyladenosine (m6A) is an abundant internal RNA modification that can impact gene expression at both post-transcriptional and transcriptional levels. However, the landscapes and functions of m6A in human brains and neurodegenerative diseases, including Alzheimer's disease (AD), are under-explored. Here, we examined RNA m6A methylome using total RNA-seq and meRIP-seq in middle frontal cortex of post-mortem brains from individuals with or without AD, which revealed m6A alteration on both...

Recent work leveraging artificial intelligence has offered promise to dissect disease heterogeneity by identifying complex intermediate brain phenotypes, called dimensional neuroimaging endophenotypes (DNEs). We advance the argument that these DNEs capture the degree of expression of respective neuroanatomical patterns measured, offering a dimensional neuroanatomical representation for studying disease heterogeneity and similarities of neurologic and neuropsychiatric diseases. We investigate the...

Disruption in neuronal and synaptic metabolic homeostasis is a key driver of neurodegeneration in Parkinson's disease (PD). Mitochondrial activity, biomass, and efficiency are critical to this balance. While activity and biomass are well characterized in PD pathology, mitochondrial metabolic efficiency remains insufficiently explored. Our previous studies showed that the protein product of PD-associated gene DJ-1 modulates metabolic efficiency through its interaction with the F1Fo-ATP-synthase β...

Duplication of the SNCA gene (SNCA^(Dupl)), linked to elevated levels of α-synuclein (aSyn), is a genetic cause of Parkinson's disease (PD). Our prior work with human-induced pluripotent stem cell (hiPSC)-derived midbrain neurons generated from patients with PD SNCA^(Dupl) identified neuritic deficits, accompanied by decreased levels of cytoskeletal element β-tubulin-III (bTubIII). To explore mechanisms underlying these effects in SNCA^(Dupl) neurons, we used CRISPR-Cas9 to generate isogenic...

The age-associated neurodegenerative disorder, Lewy body dementia (LBD), encompasses neuropsychiatric symptom-overlapping Dementia with Lewy bodies (DLB) and Parkinson's Disease with Dementia (PDD). We characterised how differential mitochondrial DNA (mtDNA) profiles contribute to neurotype-specific neurodegeneration and thereby clinicopathological heterogeneity, between LBD's syndromes. We further characterised key nuclear-encoding genes' recalibrations in response to such mtDNA changes. In...

Fatigue is a nonmotor symptom that negatively affects Parkinson's disease (PD) patients' quality of life. The study of fatigue is complex and the brain functional neural underpinnings of fatigue in PD are yet to be clarified. The aim of this study was to investigate the functional connectivity (FC) of the fatigue brain network in PD-related fatigue symptomatology. Forty-nine PD patients, divided into PD patients with fatigue (PD-f) and PD patients with no fatigue (PD-nf), and 33 healthy controls...

Advancements in human induced pluripotent stem cell (hiPSC) technology have enabled co-culture models for disease modeling in physiologically relevant systems. However, co-culturing protocols face challenges in usability and consistency. Here, we introduce a robust, reproducible hiPSC-derived co-culture system integrating astrocytes, neurons, and microglia. This model leverages cryopreserved cells, enabling co-cultures within 20 days post-thaw. Comparing monocultures and tricultures, we...

The role of beta band activity in cortico-basal ganglia interactions during motor control has been studied extensively in resting-state and for simple movements, such as button pressing. However, little is known about how beta oscillations change and interact in more complex situations involving rapid changes of movement in various contexts. To close this knowledge gap, we combined magnetoencephalography (MEG) and local field potential recordings from the subthalamic nucleus (STN) in Parkinson's...

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Defining how amyloid-β and pTau together lead to neurodegeneration is fundamental to understanding Alzheimer's disease (AD). We used imaging mass cytometry to identify neocortical neuronal subtypes lost with AD in post-mortem brain middle temporal gyri from non-diseased and AD donors. Here we showed that L5,6 RORB^(+)FOXP2^(+) and L3,5,6 GAD1^(+)FOXP2^(+) neurons, which accumulate amyloid-β intracellularly from early Braak stages, are selectively vulnerable to degeneration in AD, while L3...

Mitophagy, the selective autophagic elimination of mitochondria, is essential for maintaining mitochondrial quality and cell homeostasis. Impairment of mitophagy flux, a process involving multiple sequential intermediates, is implicated in the onset of numerous neurodegenerative diseases. Screening mitophagy inducers, particularly understanding their impact on mitophagic intermediates, is crucial for neurodegenerative disease treatment. However, existing techniques do not allow simultaneous...

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Simultaneously monitoring glutamate (Glu) dynamic at edge of synaptic cleft and peri-soma is crucial for understanding Glu-related pathology. Here, we created an electrochemical Glu sensors toolkit with spatial resolution of ∼60 nm, combining biologically engineered Glu binding protein for specifically capturing Glu together with chemically designed ferrocene groups for signal labeling. Modulation conjugation approach between GluR and ferrocene significantly improved sensitivity up to 32-folds....

Increased kinase activity of leucine-rich repeat kinase 2 (LRRK2) is associated with Parkinson's disease (PD). Numerous LRRK2-selective type I kinase inhibitors have been developed, and some have entered clinical trials. Here, to our knowledge, we present the first type II kinase inhibitors that target LRRK2. Targeting the inactive conformation of LRRK2 is functionally distinct from targeting the active-like conformation using type I inhibitors. We designed these inhibitors with a combinatorial...

The ability to distinguish strangers from familiar individuals is crucial for the survival of most mammalian species. In humans, an inability to recognize kin and familiar individuals and engage in appropriate behaviors is associated with several types of dementia, including Alzheimer's disease. Mice preferentially spend more time investigating a novel individual relative to a familiar individual. Yet, how social novelty-related information drives increased investigation of the novel animal...

DJ-1/PARK7 is the causative gene for hereditary recessive Parkinson's disease. Recent studies have reported that DJ-1 hydrolyzes cyclic 3-phosphoglyceric anhydride (cPGA), a highly reactive metabolite. However, the molecular mechanisms underlying cPGA hydrolase activity have yet to be fully elucidated. To gain a more comprehensive understanding of this activity in DJ-1, we performed molecular simulations that predicted how DJ-1 recognizes and hydrolyzes cPGA. The accuracy of these structural...

Dysregulation of dendritic spine dynamics, a process essential for synaptic plasticity and memory, is a hallmark of Alzheimer's disease (AD). Actin dynamics, largely regulated by the LIMK1-cofilin pathway, are central to maintaining structural and functional stability in neurons. In healthy brains, the LIMK1-cofilin-actin axis modulates actin polymerization within dendritic spines, supporting spine growth and plasticity. However, in AD, this pathway is altered, leading to both actin and synaptic...

Synaptic dysfunction exists before symptoms occur in Parkinson's disease, and restoring synaptic function as a promising therapeutic approach. Brain-derived neurotrophic factor serves as a key neuroregulatory factor in regulating synaptic function. Studies have shown that the protein levels of brain-derived neurotrophic factor is low in Parkinson's disease mice. However, repetitive transcranial magnetic stimulation (rTMS) can mitigate this decline. We explored the protective role of rTMS on...