Alzheimer & Parkinson

Similarities to molecular mechanisms underlying prion diseases may help to refine Alzheimer's disease therapies.

Autophagy, a lysosome-dependent protein degradation mechanism, is a highly conserved catabolic process seen in all eukaryotes. This cell protection system, which is present in all tissues and functions at a basic level, can be up- or downregulated in response to various stresses. A disruption in the natural route of the autophagy process is frequently followed by an interruption in the inherent operation of the body's cells and organs. Probiotics are live bacteria that protect the host through...

Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by the aggregation of β-amyloid (Aβ) and tau in the brain. Breakthroughs in disease-modifying treatments targeting Aβ bring new hope for the management of AD. But to effectively modify and someday even prevent AD, a better understanding is needed of the biological mechanisms that underlie and link Aβ and tau in AD. Developments of high-throughput omics, including genomics, proteomics, and transcriptomics,...

Alzheimer's disease (AD) presents a significant challenge in neurodegenerative research and clinical practice due to its complex etiology and progressive nature. The integration of artificial intelligence (AI) into the diagnosis, treatment, and prognostic modelling of AD holds promising potential to transform the landscape of dementia care. This review explores recent advancements in AI applications across various stages of AD management. In early diagnosis, AI-enhanced neuroimaging techniques,...

Animal and computational models of Alzheimer's disease (AD) indicate that early amyloid-β (Aβ) deposits drive neurons into a hyperactive regime, and that subsequent tau depositions manifest an opposite, suppressive effect as behavioral deficits emerge. Here we report analogous changes in macroscopic oscillatory neurophysiology in the human brain. We used positron emission tomography and task-free magnetoencephalography to test the effects of Aβ and tau deposition on cortical neurophysiology in...

Apolipoprotein E4 (ApoE4), the strongest genetic risk factor for sporadic Alzheimer's disease, is also a risk factor for microvascular pathologies leading to cognitive impairment, particularly subcortical white matter injury. These effects have been attributed to alterations in the regulation of the brain blood supply, but the cellular source of ApoE4 and the underlying mechanisms remain unclear. In mice expressing human ApoE3 or ApoE4, we report that border-associated macrophages (BAMs),...

Early in Alzheimer's disease (AD), pericytes constrict capillaries, increasing their hydraulic resistance and trapping of immune cells and, thus, decreasing cerebral blood flow (CBF). Therapeutic approaches to attenuate pericyte-mediated constriction in AD are lacking. Here, using in vivo two-photon imaging with laser Doppler and speckle flowmetry and magnetic resonance imaging, we show that Ca^(2+) entry via L-type voltage-gated calcium channels (CaVs) controls the contractile tone of...

It is well established that DNA Damage Regulated Autophagy Modulator 1 (DRAM1), a lysosomal protein and a target of p53, participates in autophagy. The cellular functions of DRAM1 beyond autophagy remain elusive. Here, we show p53-dependent upregulation of DRAM1 in mitochondrial damage-induced Parkinson's disease (PD) models and exacerbation of disease phenotypes by DRAM1. We find that the lysosomal location of DRAM1 relies on its intact structure including the cytosol-facing C-terminal domain....

Glycogen synthase kinase-3α/β (GSK3α/β) is a critical kinase for Tau hyperphosphorylation which contributes to neurodegeneration. Despite the termination of clinical trials for GSK3α/β inhibitors in Alzheimer's disease (AD) treatment, there is a pressing need for novel therapeutic strategies targeting GSK3α/β. Here, we identified the compound AS1842856 (AS), a specific forkhead box protein O1 (FOXO1) inhibitor, reduced intracellular GSK3α/β content in a FOXO1-independent manner. Specifically, AS...

Cuprous copper [Cu(I)] is an essential cofactor for enzymes that support many fundamental cellular functions including mitochondrial respiration and suppression of oxidative stress. Neurons are particularly reliant on mitochondrial production of ATP, with many neurodegenerative diseases, including Parkinson's disease, associated with diminished mitochondrial function. The gene MBLAC1 encodes a ribonuclease that targets pre-mRNA of replication-dependent histones, proteins recently found in yeast...

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Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that is a disease-modifying drug candidate for Parkinson's disease. CDNF has pleiotropic protective effects on stressed cells, but its mechanism of action remains incompletely understood. Here, we use state-of-the-art advanced structural techniques to resolve the structural basis of CDNF interaction with GRP78, the master regulator of the unfolded protein response (UPR) pathway. Subsequent binding studies...

Parkinson's disease (PD) is typically a sporadic late-onset disorder, which has made it difficult to model in mice. Several transgenic mouse models bearing mutations in SNCA, which encodes alpha-Synuclein (α-Syn), have been made, but these lines do not express SNCA in a physiologically accurate spatiotemporal pattern, which limits the ability of the mice to recapitulate the features of human PD. Here, we generated knock-in mice bearing the G51D SNCA mutation. After establishing that their motor...

Recent research has illuminated the profound bidirectional communication between the gastrointestinal tract and the brain, furthering our understanding of neurological ailments facilitating possible therapeutic strategies. Technological advancements in high-throughput sequencing and multi-omics have unveiled significant alterations in gut microbiota and their metabolites in various neurological disorders. This review provides a thorough analysis of the role of microbiome-gut-brain axis in...

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Cognitive frailty (CF) is the conjunction of cognitive impairment without dementia and physical frailty. While predictors of each element are well-researched, mechanisms of their co-occurrence have not been integrated, particularly in terms of relationships between social, psychological, and biological factors. This interdisciplinary scoping review set out to categorise a heterogenous multidisciplinary literature to identify potential pathways and mechanisms of CF, and research gaps. Studies...

Protein aggregation causes a wide range of neurodegenerative diseases. Targeting and removing aggregates, but not the functional protein, is a considerable therapeutic challenge. Here, we describe a therapeutic strategy called "RING-Bait," which employs an aggregating protein sequence combined with an E3 ubiquitin ligase. RING-Bait is recruited into aggregates, whereupon clustering dimerizes the RING domain and activates its E3 function, resulting in the degradation of the aggregate complex. We...

Numerous eukaryotic toxins that accumulate in geophytic plants are valuable in the clinic, yet their biosynthetic pathways have remained elusive. A notable example is the >150 Amaryllidaceae alkaloids (AmAs), including galantamine, an FDA-approved treatment for Alzheimer's disease. We show that while AmAs accumulate to high levels in many daffodil tissues, biosynthesis is localized to nascent, growing tissue at the leaf base. A similar trend is found in the production of steroidal alkaloids...

Identifying concomitant Lewy body (LB) pathology through seed amplification assays (SAA) might enhance the diagnostic and prognostic work-up of Alzheimer's disease (AD) in clinical practice and trials. This study examined whether LB pathology exacerbates AD-related disease progression in 795 cognitively impaired individuals (Mild Cognitive Impairment and dementia) from the longitudinal multi-center observational ADNI cohort. Participants were on average 75 years of age (SD = 7.89), 40.8% were...