Alzheimer & Parkinson

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the second most common cause of autosomal-dominant Parkinson's disease (PD), and increased LRRK2 kinase activity is also observed in idiopathic PD, making LRRK2 a major actionable therapeutic target. LRRK2 is a 286-kDa multidomain enzyme containing a Ras-like GTPase (ROC) and a kinase domain. Using cryo-electron microscopy (cryo-EM), biochemical reconstitution, and cell-based assays, we show that the ROC GTPase governs switching between...

Deficiencies in glucocerebrosidase (GCase) are associated with Parkinson's disease (PD). The mechanistic basis of this association is being intensively investigated, and new treatments are being developed aiming to boost brain GCase activity in patients. Despite the importance of GCase in PD, studies are hampered by the continued reliance on weak and non-selective inhibitors like conduritol B epoxide. Here, we report easily prepared and selective irreversible inhibitors and complementary...

Parkinson's disease is characterized by dopaminergic neuron loss and accumulation of α-synuclein aggregates in the brain. G51D α-synuclein knock-in mice provide a genetically and clinically relevant model of disease, exhibiting early olfactory deficits, age-dependent motor impairment, and progressive phospho-α-synuclein accumulation. In multiple Parkinson's disease models, striatal cholinergic and parvalbumin interneurons, as well as astrocytes, lose primary cilia and the neurotrophic signaling...

Microglia, the resident macrophages of the central nervous system (CNS), are key players in maintaining brain and spinal cord homeostasis and protecting the CNS from damage and disease. During aging, the brain undergoes profound changes-including chronic low-grade inflammation, synaptic dysfunction, and increased vulnerability to neurodegenerative diseases-all of which are closely related to alterations in microglial function. One emerging theme is that microglial metabolism is a crucial...

Astrocytes and APOE are strongly implicated in Alzheimer's disease (AD), yet the impact of astrocytes carrying different APOE variants on AD hallmarks remains incompletely understood. Here, we generate a chimeric model of AD by transplanting isogenic APOE3 or APOE4 human induced pluripotent stem cell-derived astrocyte progenitors into neonatal AD mice. Donor cells differentiate into human astrocytes that integrate into the cortex and display morphologies consistent with interlaminar-like...

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Central nervous system (CNS) disorders are fundamentally linked to metabolic dysregulation within immune and glial cells. This review provides a systematic synthesis of immunometabolic reprogramming-encompassing glucose, lipid, and amino acid metabolism, and oxidative phosphorylation-in CNS-resident microglia, immunomodulatory astrocytes, and peripherally infiltrating immune cells (T cells, B cells, and neutrophils) across Alzheimer's disease, Parkinson's disease, multiple sclerosis, and...

The dominantly inherited Flemish mutation-an A692G substitution in the amyloid precursor protein, corresponding to an A21G change in amyloid-β (Aβ)-causes a rare, early-onset form of Alzheimer disease characterized by pronounced cerebral amyloid angiopathy and unusually large senile plaque cores. Here, we report cryo-electron microscopy structures of amyloid filaments extracted from the postmortem parietal lobes of two individuals representing the only two known Flemish pedigrees worldwide....

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Hyperphosphorylation and aggregation of tau are pathological hallmarks of tauopathies. Mitochondrial dysfunction is also a common feature of tauopathies. The mechanistic link between tau abnormalities and mitochondrial dysfunction and its relationship to the physiological function of tau, however, is unclear. Here, we demonstrate that tau regulates mitochondrial reverse electron transport (RET), which produces excess reactive oxygen species (ROS), reduces the NAD^(+)/NADH ratio, and is activated...

Alzheimer's disease (AD) is a slow-progressing neurodegenerative disease, mainly characterized by the accumulation of amyloid beta (Aβ) plaques and intracellular hyperphosphorylated Tau protein, along with the generation of free radicals. In normal physiology free radicals play a promising role. However, the imbalance in the formation and clearance of the free radicals or reactive oxygen species/reactive nitrogen species (ROS/RNS) disrupts redox homeostasis, resulting in oxidative stress....

The primary mechanism and subcellular localisation of α-synuclein toxicity in Parkinson's disease pathogenesis remain unknown. We spatially and temporally resolved proteomic and transcriptomic changes in human iPSC-derived dopaminergic neurons with increasing burden of pathological α-synuclein. We found that misfolded α-synuclein proteoforms, signified by the formation of nanoscale intraneuronal puncta, are associated with impaired translocon function at the endoplasmic reticulum (ER). We show...

Mutations in lysosomal enzyme glucocerebrosidase (GBA), the most common genetic risk factor for Parkinson disease (PD), exacerbate α-synuclein pathology through unclear mechanisms. Here, we report, in a large cohort, that GBA-mutated PD patients exhibit lower serum cholesterol levels. By introducing the most common GBA variant in our cohort, L444P, into human α-synuclein knock-in mice, we noted that the mice exhibited behavioral and molecular pathological PD features at 12 months of age....

Mitochondrial dysfunction and abnormal energy metabolism are important pathological features of Alzheimer's disease (AD). This study investigates how mitochondrial protease YME1L1 affects mitochondrial function and its upstream regulation in the pathogenesis of AD. The AD model was established by using APP/PS1 transgenic mice, primary neurons treated with Aβ1-42, and HT22 cells. The silencing of YME1L1 was achieved to evaluate its effects on mitochondrial function and OPA1 protein hydrolysis....

Parkinson's disease (PD) is a multisystemic disorder that manifests through motor and non-motor symptoms. Motor dysfunction results from the degeneration of dopamine-producing neurons in the substantia nigra pars compacta. Increasing evidence suggests that synapse dysfunction precedes neuronal loss by years. Still, early synaptic alterations in PD remain poorly understood. Here, we integrate literature meta-analysis and multi-omics with biochemical, imaging, and electrophysiological measurements...

SQSTM1/p62 (sequestosome 1) is an important receptor protein involved in many cellular signaling processes, including macroautophagy/autophagy. It is a molecular hub for cellular homeostasis and cellular responses. Within autophagy, SQSTM1 targets ubiquitinated cargo for degradation, maintaining cellular proteostasis. Structurally, SQSTM1 consists of several domains that facilitate its binding to ubiquitinated cargo, the formation of SQSTM1 aggregate inclusions, interactions with MAP1LC3/LC3,...

Microglia are key players in Alzheimer's disease, but the transcriptional control of their phagocytic function remains unclear. Kim et al. show that mouse microglial Spi1 deletion worsens amyloid pathology by impairing Aβ clearance through Syk, Lyn, and Fcgr1, providing new insight into PU.1-dependent regulatory networks and microglial functions in neurodegeneration.

Increasing evidence indicates that shifts in brain polysaccharide metabolism can influence the progression of multiple neurodegenerative diseases. Here, we profile corpora amylacea (CA) in 230 postmortem human brains, revealing significantly higher densities in Alzheimer's disease (AD) patients when compared with patients with other or no neurodegenerative diseases and a tight correlation of CA density with neurofibrillary tangle (NFT) pathology. Immunohistochemical profiling using an...

Alzheimer's disease (AD) exhibits substantial clinical and pathological heterogeneity that is not fully explained by amyloid-β and tau pathology alone. TAR DNA-binding protein 43 (TDP-43) is increasingly recognized as a frequent copathology in AD, particularly in limbic regions, where its presence is associated with accelerated cognitive decline. Disruption of mitochondrial homeostasis is also an early and consistent feature of AD and contributes to neuronal vulnerability. In this review, we...

We investigated how patients with Parkinson's disease (PD) manage the explore-exploit trade-off in a structured reward-learning task. Patients were tested either on (n = 34) or off (n = 34) dopaminergic medication (levodopa), with age-matched polyneuropathy patients serving as controls (n = 35). Behaviorally, patients off medication showed marked learning and decision-making deficits, characterized by overexploration (excessive sampling of novel options) and insufficient exploitation...