Neuroinflammation plays a critical role in the pathogenesis of neurodegenerative diseases, particularly in Huntington's disease (HD) and Alzheimer's disease (AD). In HD, studies have shown that microglial activation and the localization of complement proteins are associated with the early loss of corticostriatal synapses, which correlates with cognitive dysfunction in patients. Specifically, postmortem analyses revealed that elevated levels of complement proteins in cerebrospinal fluid correspond with disease burden in premanifest HD patients, suggesting that innate immune mechanisms are pivotal in synaptic elimination during the early stages of the disease (ref: Wilton doi.org/10.1038/s41591-023-02566-3/). Furthermore, the review of innate immune mechanisms in HD highlights the complexity of neuroinflammation, indicating that it may arise from both neuronal dysfunction and cell-autonomous immune cell phenotypes (ref: Unknown doi.org/10.1038/s41591-023-02616-w/). In the context of AD, the role of apolipoprotein E (APOE) is emphasized, where the APOE4 isoform restricts microglial activation, thereby impacting brain homeostasis and exacerbating AD pathology (ref: Liu doi.org/10.1038/s41590-023-01640-9/). These findings collectively underscore the intricate interplay between neuroinflammation and synaptic integrity in neurodegenerative diseases, suggesting potential therapeutic targets within the immune response pathways.

The molecular mechanisms underlying Alzheimer's disease (AD) have garnered significant attention, particularly regarding the role of amyloid-beta precursor protein (APP) and tau protein in disease progression. Recent research has identified that the interaction between APP and Fe65 protein triggers the secretion of amyloid-beta, which is central to AD pathogenesis. Targeting this interaction presents a promising therapeutic avenue (ref: Iyaswamy doi.org/10.1038/s41392-023-01657-4/). Additionally, the investigation of tau oligomers has revealed their association with excessive synapse elimination by microglia and astrocytes, which correlates with cognitive decline in dementia (ref: Taddei doi.org/10.1001/jamaneurol.2023.3530/). Biomarkers also play a crucial role in early detection; a study demonstrated that plasma levels of Aβ42, p-tau181, and neurofilament light chain (NfL) can predict preclinical AD up to eight years before clinical onset, highlighting their potential utility in early diagnosis (ref: Cai doi.org/10.1038/s41467-023-42596-6/). These insights into molecular mechanisms and biomarkers not only enhance our understanding of AD pathology but also pave the way for developing targeted interventions.

Genetic factors significantly influence the risk and progression of neurodegenerative diseases, as evidenced by recent studies exploring various genetic modifiers. In amyotrophic lateral sclerosis (ALS), genome-wide analyses have identified NEAT1 as a genetic modifier of age at onset, suggesting that its expression levels may correlate with disease progression (ref: Li doi.org/10.1186/s13024-023-00669-6/). Additionally, the role of apolipoprotein E (APOE) continues to be a focal point in AD research, where the APOE4 allele is associated with increased risk and altered microglial responses, further complicating the disease landscape (ref: Liu doi.org/10.1038/s41590-023-01640-9/). Furthermore, the influence of environmental factors, such as microbiota transfer between cohabitants, has been proposed as a potential risk factor for dementia, indicating that both genetic predispositions and lifestyle factors contribute to neurodegenerative disease risk (ref: Endres doi.org/10.1038/s41582-023-00894-z/). These findings highlight the multifaceted nature of genetic and environmental interactions in neurodegenerative diseases, emphasizing the need for comprehensive risk assessment strategies.

Innovative therapeutic approaches are emerging in the field of neurodegenerative diseases, particularly with advancements in stem cell therapies and neuromodulation techniques. The STEM-PD trial is pioneering the use of human embryonic stem cell-derived dopaminergic neurons for treating Parkinson's disease, with preclinical data supporting its safety and efficacy (ref: Kirkeby doi.org/10.1016/j.stem.2023.08.014/). Additionally, the development of magnetically manipulated optoelectronic hybrid microrobots represents a novel strategy for targeted non-genetic neuromodulation, potentially enhancing treatment precision for neurological disorders (ref: Gao doi.org/10.1002/adma.202305632/). These advancements are complemented by the exploration of laminin-coated electronic scaffolds that promote neural regeneration and track brain cell migration post-injury, indicating a shift towards more integrated and responsive therapeutic modalities (ref: Yang doi.org/10.1038/s41551-023-01101-6/). Collectively, these innovations reflect a promising trajectory in the development of effective treatments for neurodegenerative diseases.

Understanding the relationship between cognitive function and neurodegeneration is critical for developing effective interventions. Recent studies have focused on reconstructing disease dynamics to provide mechanistic insights into cognitive decline associated with neurodegenerative diseases. The TimeAx algorithm has been introduced to capture the complexities of disease progression using high-dimensional, short time-series data, which could enhance diagnostic and therapeutic strategies (ref: Frishberg doi.org/10.1038/s41467-023-42354-8/). Additionally, the role of lipid aggregation in amyloidogenic diseases, including AD, has been highlighted, suggesting that misfolded proteins may trigger cognitive impairments through toxic oligomer formation (ref: Kurouski doi.org/10.1021/acs.accounts.3c00386/). These findings underscore the importance of integrating cognitive assessments with molecular and dynamic disease models to better understand and address the cognitive aspects of neurodegeneration.

Synaptic dysfunction is a hallmark of various neurodegenerative diseases, with recent studies elucidating the mechanisms underlying synapse loss. In Huntington's disease, research has demonstrated that microglial activation and complement protein localization are critical for the early loss of corticostriatal synapses, which correlates with cognitive dysfunction (ref: Wilton doi.org/10.1038/s41591-023-02566-3/). Similarly, in Alzheimer's disease, the accumulation of tau oligomers has been linked to excessive synapse elimination by microglia and astrocytes, with significant differences observed in synaptic integrity between individuals with dementia and resilient individuals (ref: Taddei doi.org/10.1001/jamaneurol.2023.3530/). These findings highlight the interconnectedness of synaptic health and cognitive function, suggesting that targeting synaptic preservation may be a viable therapeutic strategy in neurodegenerative diseases.

Advancements in neurodegenerative disease models are crucial for understanding disease mechanisms and developing effective therapies. Recent studies have focused on the role of microglial morphology in neuroinflammation, revealing that polarized microtubule remodeling transforms reactive microglia and drives cytokine release, which may contribute to neurodegenerative pathology (ref: Adrian doi.org/10.1038/s41467-023-41891-6/). Additionally, the amplification of α-synuclein aggregates from patient-derived Lewy bodies has been shown to recapitulate Lewy body diseases in mice, providing a valuable model for studying disease progression and potential therapeutic interventions (ref: Uemura doi.org/10.1038/s41467-023-42705-5/). Furthermore, the cGAS-STING pathway has been implicated in inflammaging-associated neurodegeneration, highlighting the role of innate immune responses in aging and neurodegenerative diseases (ref: Izquierdo doi.org/10.1186/s13024-023-00666-9/). These models and mechanisms are essential for advancing our understanding of neurodegenerative diseases and guiding the development of targeted therapies.