Alzheimer & Parkinson

The endoplasmic reticulum (ER) is a central organelle that coordinates protein synthesis and processing, lipid metabolism, Ca²⁺ storage, detoxification, and cellular homeostasis. These processes are rigorously regulated, and when the ER encounters external stimuli, it triggers ER stress, a main mechanism that plays a crucial role in determining cellular fate. In addition to its role in apoptosis, further research has unveiled novel physiological functions of ER stress, encompassing its...

Neurodegenerative diseases are marked by progressive neuronal damage and currently lack a cure. Recently, exercise has emerged as a promising non-pharmacological approach to potentially slow disease progression and enhance cognitive function. This narrative review summarizes the effects of various exercise modalities-including aerobic exercise, resistance training, and balance training-on four major neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, and...

Synaptic dysfunction in Alzheimer's disease (AD) may drive synapse loss and cognitive impairment. Whether AD-related synaptic pathophysiology occurs globally, or in specific synapses, is unclear. We investigate in vivo AD-related synaptic dysfunction during early-stage amyloidosis in App^(NL-G-F) mice. We find reduced presynaptic GABAergic proteins at c-Fos-positive excitatory neurons and increased calcium-mediated activity at excitatory and inhibitory neuronal assemblies. In vivo synaptic...

Lecanemab, an anti-amyloid antibody, has demonstrated a significant clinical benefit in slowing cognitive decline in early Alzheimer's disease (AD). A mechanistic Neuro-Dynamic Quantitative Systems Pharmacology (QSP) model was developed to capture the temporal and biological complexity of AD progression. This QSP model incorporates three interlinked modules reflecting core aspects of AD pathology: Aβ accumulation, tau pathology, and cognitive decline, where Aβ accumulation promotes tau...

Aging is a primary risk factor for chronic diseases, with cellular senescence as an effective target to delay, prevent or alleviate age-related disorders. Here we report in vitro screening outputs from a natural medicinal agent library, wherein dihydromyricetin, a natural flavonoid, showed senotherapeutic potential. Dihydromyricetin protects senescent fibroblasts against further DNA damage and attenuates the senescence-associated secretory phenotype, acting as a senomorphic agent. Proteomics...

Aging involves multiple detrimental changes in the systemic milieu, leading to functional deterioration and age-related diseases. However, the potential self-protective adaptive alterations during aging remain underexplored. Here we show that phosphoenolpyruvate (PEP), a glycolytic metabolite, acts as a protective factor against age-related chronic inflammation. Longitudinal analyses in mice and humans reveal a biphasic PEP trajectory, characterized by initial accumulation followed by...

In Alzheimer's disease, many surviving neurons with tau pathology contain granulovacuolar degeneration bodies (GVBs), neuron-specific lysosomal structures induced by pathological tau assemblies. This could indicate a neuroprotective role for GVBs; however, the mechanism of GVB formation and its functional implications are elusive. Here, we demonstrate that casein kinase 1δ (CK1δ) activity is required for GVB formation. CK1δ is sequestered in the GVB during this process in an autophagy-dependent...

Alzheimer's disease (AD) is the leading cause of dementia and is characterized by progressive amyloid accumulation followed by tau-mediated neurodegeneration. Despite advances in anti-amyloid immunotherapies, important limitations remain, highlighting the need for new therapeutic strategies. Here, we introduce anti-amyloid chimeric antigen receptors expressed in astrocytes (CAR-A) and validate their function in vitro. We show that two CAR-A designs reduce amyloid and associated pathology after...

Genetically altered astrocytes reduce a cardinal pathological feature of Alzheimer's disease.

MS4A4A and MS4A6A are microglia-expressed genes linked to Alzheimer's disease risk. In this issue of Neuron, Rosner et al.¹ show that these proteins cooperatively restrain TREM2 signaling, dampening protective microglial responses and highlighting MS4A inhibition as a potential strategy to rejuvenate the brain's innate immune system in Alzheimer's disease.

Lewy bodies, a pathological hallmark of Parkinson's disease, are α-synuclein-enriched cytoplasmic inclusions that drive progressive neurodegeneration. A long-standing yet unmet goal has been the visualization of α-synuclein (α-Syn) inclusions in live brain and measurements of their pathological effects on individual neurons. Here, we developed genetically encoded reporters and knock-in mouse lines to achieve this goal. The reporters exhibited a 5-fold increase in fluorescence upon incorporation...

Trained immunity is the ability of the innate immune system to mount a heightened response to an environmental stimulus after a previous encounter with a noxious trigger. This effect is mediated by metabolic rewiring and epigenetic reprogramming in innate immune cells. In the context of neuroinflammation, trained immunity may represent a major contributor to the pathogenesis of neurological diseases, exerting both detrimental and potentially beneficial effects. While the general mechanisms and...

The hippocampus is crucial to learning and memory, functions that decline with age due to impaired mitochondrial bioenergetics and reduced mitophagy, resulting in the accumulation of dysfunctional mitochondria and increased susceptibility to neurodegeneration. Urolithin A (UA), a natural mitophagy activator derived from polyphenols, has demonstrated benefits in Alzheimer's disease models; however, its role in normal aging remains unclear. Here, we investigated whether UA can prevent or reverse...

Young-onset Parkinson's disease (PD), the most common autosomal recessive familial PD, is caused by gene mutations in Parkin (PRKN). These mutations result in Parkin protein loss and reduced enzymatic activity, leading to severe degeneration of dopamine-producing neurons in the substantia nigra pars compacta (SNpc). Adeno-associated virus (AAV) gene therapy can directly address the cause of PRKN-PD by expressing Parkin protein at levels comparable to those observed in healthy humans. AAV9...

Triggering receptor expressed on myeloid cells 2 (TREM2) regulates microglial function and is implicated in Alzheimer's disease (AD) pathogenesis. Here we conducted a phase 2, randomized, double-blind, placebo-controlled trial of a humanized TREM2 agonistic monoclonal antibody in 381 participants with early AD. Participants were randomized (1:1:1:1) to receive AL002 (15 mg kg^(-1), 40 mg kg^(-1) or 60 mg kg^(-1)) or placebo intravenously every 4 weeks for 48-96 weeks. AL002 demonstrated...

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Clearance of aberrant cerebral amyloid-β (Aβ) deposits represents a promising therapeutic strategy for Alzheimer's disease (AD), yet current anti-Aβ immunotherapy raises safety concerns due to frequent adverse effects. Extracellular targeted protein degradation (eTPD) offers an approach for safe and efficient clearance of disease-causing proteins. Here, we develop a next-generation eTPD platform, synthetic peptide-programmed lysosome-targeting chimeras (SPYTACs), using entirely synthesized...

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Parkinson's disease (PD) is a prevalent neurodegenerative disorder predominantly affecting individuals over 60. Its motor symptoms stem from the deterioration of dopaminergic neurons within the substantia nigra. Despite aging being a significant risk factor, the specific mechanisms linking aging and PD pathology remain unclear. Leveraging advancements in single-cell genomics, this study utilizes single-nucleus multiome sequencing to capture transcriptomic and epigenetic profiles from 40,125...

Alzheimer's disease (AD) is the most common neurodegenerative disorder, yet effective preventive or therapeutic strategies remain limited. A hallmark of AD pathology is the accumulation of insoluble amyloid-β (Aβ) aggregates, which are targeted by recent antibody-based therapies. Conversely, soluble amyloid precursor protein-alpha (sAPPα), a non-amyloidogenic cleavage product of APP, possesses neuroprotective, neurotrophic, and synaptogenic properties, and the ability to enhance memory. This...