Alzheimer & Parkinson

Twenty years after the discovery of induced pluripotent stem cells, the field has progressed from patient-specific disease modeling toward cell-based therapies for neurodegenerative disorders. Parkinson's disease has emerged as the leading model for neuronal replacement, whereas Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis require distinct combinations of circuit reconstruction, cellular support, immune modulation, and engineered therapeutic delivery. We discuss...

Parkinsons disease, characterized by the aggregation of alpha-synuclein is a complex neurodegenerative disorder with the fastest global prevalence growth. The identification of shared genes expressed in both blood and brain of Parkinson's disease patients improves the knowledge on peripheral pathophysiology of the disease and facilitates identification of minimally invasive potential biomarkers from these shared genes. Our study intends to identify a shared transcriptomic signature between the...

No therapies ensure long-term survival of dopaminergic neurons in Parkinson's disease. In this context, we propose that early neurodegeneration is an adaptive state of transmissive dormancy, not dysfunction. Upon sensing cellular stress, an inducible transcriptional program restricts cytosolic dopamine and actively silences neurotransmission. This adaptive response precedes neuronal death, reframing early symptoms as programmed dormancy rather than frank degeneration. Thus, reactivation...

Neurodegenerative disease is marked not just by loss of proteins or cells, but by dynamic rewiring of macromolecular interaction networks that precede and drive pathology. Here, we present a temporally resolved, systems-scale map of multi-protein complex remodeling in a tauopathy model, integrating co-fractionation mass spectrometry, quantitative phosphoproteomics, and machine learning to decode phosphorylation-dependent shifts in protein interactomes across disease progression. This...

α-synuclein is a pre-synaptic protein implicated in synucleinopathies including Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies, where it accumulates in intracellular aggregates termed Lewy bodies and Lewy neurites. Recent studies have reported that α-synuclein undergoes phase separation to form biomolecular condensates both in vitro and in mammalian cells. α-synuclein condensates are thought to contribute to disease through progressive aggregation. Here we show...

Aging and Alzheimer's disease (AD) are accompanied by alterations to large-scale communication patterns in the brain, which can be tracked in vivo using functional connectivity. The location, direction and relevance of these changes remain widely debated, although they are rarely studied in the context of whole-cortex communication dynamics. Here, in two independent cohorts (BioFINDER-2, N = 973; Alzheimer's Disease Neuroimaging Initiative, N = 129), we show that functional connectivity changes...

In Alzheimer's Disease (AD) the default mode network (DMN) exhibits selective vulnerability to functional decline and amyloid beta (Aβ) plaques in early AD. DMN vulnerability may simply be the result of Aβ accumulation. Alternately, Aβ may unmask an intrinsic susceptibility of DMN circuits. Should DMN vulnerability persist amidst global Aβ deposition, this would support the latter hypothesis. We tested this using long-term, multi-region recordings of single units in mice characterized by...

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Alternative polyadenylation (APA) has a central role in regulation of the fate of mRNA and exhibits high variability in the brain and in neurons. However, brain APA regulation has not been mapped at cell type resolution, and the genetic control of APA in brain cell types and its contribution to genetic disease have remained unclear. Here we report a single-cell atlas of APA of the aged human brain across 2 million cells from 379 human postmortem brains across individuals with and without...

Most neurodegenerative diseases are thought to spread through the brain by prion-like mechanisms, in which filamentous protein assemblies self-propagate by templated seeding¹. Distinct conformations of amyloid filaments may provide the physical basis for the strains that lead to different diseases². However, a central pillar of the prion hypothesis, that strains retain their structural identity upon transmission, has not been demonstrated. Here we show that the injection of tau filaments from...

Misfolded alpha-Synuclein (α-Syn) accumulation is the defining molecular pathology of Parkinson's disease (PD), yet blood-based assays remain challenged by the high background of peripheral α-Syn originating mainly from red blood cells. Neuronal extracellular vesicles (EVs) circulating in blood offer a biologically enriched source of brain-derived α-Syn proteoforms, but their ultralow abundance has hindered reliable detection. Here, we introduce an organic electrochemical transistor-based...

Biological aging clocks offer estimations of aging and dementia, yet scalability is limited. We introduce a large-scale, cross-national speech clock derived from 2928 individuals across five Latin American countries, spanning healthy controls (HCs), mild cognitive impairment (MCI), Alzheimer's disease (AD), and non-language/language-dominant frontotemporal dementia (nldFTD/ldFTD). Multimodal acoustic and linguistic features were trained with supervised models to estimate chronological age,...

Examination of genetic risk factors associated with neurodegenerative diseases has provided important mechanistic insights into the pathophysiology of these disorders, and it has implicated defects in lysosomal function as a key component of the neurodegenerative process. The lysosome has a primary role in mediating degradation of both intracellular contents and endocytosed material from the extracellular space. Aggregation of misfolded proteins is a pathological mechanism that is observed...

Meningeal lymphatic vessels drain brain fluid and waste into the cervical lymph nodes, but how removing these nodes during surgery affects brain health is unknown. Retrospective analysis of cancer patients who underwent neck lymphadenectomy without chemo-radiation therapy found that up to 25% developed mild-to-severe cognitive impairment, and neuroimaging showed accelerated temporal horn enlargement after bilateral surgery. To determine mechanistically how cervical lymphadenectomy contributes to...

Atherosclerosis, recognized as a prototypical age-associated vascular disease, is driven by macrophage foam cell formation. Individuals with Parkinson's disease (PD) exhibit an elevated risk for stroke. While α-synuclein (α-Syn) is known for its neuronal role in PD, its presence in the circulation and potential vascular effects remain unexplored. Here, we identify α-Syn as a previously unrecognized circulating factor that promotes atherosclerosis. α-Syn was detected in human atherosclerotic...

Tau, a neuronal microtubule-associated protein (MAP), organizes the axonal cytoskeleton, and regulates intracellular transport. Tau hyperphosphorylation is linked to neurodegeneration in tauopathies, including Alzheimer's disease. Tau binds microtubules cooperatively to form cohesive envelopes, which are thought to control access to the microtubule lattice and regulate the activity of motor proteins and other MAPs. However, how disease-related perturbations affect tau dynamics and its function...

Bcl-2-associated athanogene 3 (BAG3) is a mediator of chaperone-assisted selective autophagy, and in the brain, is most highly expressed in astrocytes. However, its role in astrocytes remains poorly defined. Given the genetic and pathological links of BAG3 to proteostasis and neurodegenerative diseases, we investigated how BAG3 contributes to astrocyte function and Alzheimer's disease (AD). To define its function and relevance, we used single-nucleus RNA sequencing to confirm BAG3 enrichment in...

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, and dysfunction of triggering receptor expressed on myeloid cells 2 (TREM2) in microglia increases AD risk. TREM2 activation promotes protective microglial functions and mitigates AD pathology. Although TREM2-activating antibodies show therapeutic potential, the mechanisms underlying TREM2-mediated rescue effects remain unclear. Here, we show that two TREM2-activating single-domain antibodies (sdAbs), 10C11 and 10E12,...

Caspase-3, a cysteine-aspartic protease canonically known for its role in apoptotic cell death, has been implicated in several non-apoptotic functions, particularly in microglia, the brain-resident macrophages. These novel functions appear to depend on distinct levels of caspase-3 activation; however, the role of basal caspase-3 activity remains unclear. Here, we show that basal caspase-3 regulates RNA splicing in microglia, and its deficiency in a Parkinson´s disease (PD) model leads to...

Navigation in the real world may rely on a multitude of strategies with distinct advantages and disadvantages; however, the characterization of spontaneous strategy use is scarce. We explore data across three groups engaged in virtual navigation: patients with epilepsy undergoing invasive electrophysiological recordings, two groups undergoing fMRI scanning: young adults at genetic risk for Alzheimer's disease (APOE-ε4 carriers), and healthy controls. We establish metrics to quantitatively...