As the most common dementia, Alzheimer's disease (AD) exacts an immense personal, societal, and economic toll. AD was first described at the neuropathological level in the early 1900s. Today, we have ...mechanistic insight into select aspects of AD pathogenesis and have the ability to clinically detect and diagnose AD and underlying AD pathologies in living patients. These insights demonstrate that AD is a complex, insidious, degenerative proteinopathy triggered by Aβ aggregate formation. Over time Aβ pathology drives neurofibrillary tangle (NFT) pathology, dysfunction of virtually all cell types in the brain, and ultimately, overt neurodegeneration. Yet, large gaps in our knowledge of AD pathophysiology and huge unmet medical need remain. Though we largely conceptualize AD as a disease of aging, heritable and non-heritable factors impact brain physiology, either continuously or at specific time points during the lifespan, and thereby alter risk for devolvement of AD. Herein, I describe the lifelong journey of a healthy brain from birth to death with AD, while acknowledging the many knowledge gaps that remain regarding our understanding of AD pathogenesis. To ensure the current lexicon surrounding AD changes from inevitable, incurable, and poorly manageable to a lexicon of preventable, curable, and manageable we must address these knowledge gaps, develop therapies that have a bigger impact on clinical symptoms or progression of disease and use these interventions at the appropriate stage of disease.
Scientific advances over the last four decades have steadily infused the Alzheimer’s disease (AD) field with great optimism that therapies targeting Aβ, amyloid, tau, and innate immune activation ...states in the brain would provide disease modification. Unfortunately, this optimistic scenario has not yet played out. Though a recent approval of the anti-Aβ aggregate binding antibody, Aduhelm (aducanumab), as a “disease-modifying therapy for AD” is viewed by some as a breakthrough, many remain unconvinced by the data underlying this approval. Collectively, we have not succeeded in changing AD from a largely untreatable, inevitable, and incurable disease to a treatable, preventable, and curable one. Here, I will review the major foci of the AD “disease-modifying” therapeutic pipeline and some of the “open questions” that remain in terms of these therapeutic approaches. I will conclude the review by discussing how we, as a field, might adjust our approach, learning from our past failures to ensure future success.
In multiple neurodegenerative diseases, including Alzheimer's disease (AD), a prominent pathological feature is the aberrant aggregation and inclusion formation of the microtubule-associated protein ...tau. Because of the pathological association, these disorders are often referred to as tauopathies. Mutations in the MAPT gene that encodes tau can cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), providing the clearest evidence that tauopathy plays a causal role in neurodegeneration. However, large gaps in our knowledge remain regarding how various FTDP-17-linked tau mutations promote tau aggregation and neurodegeneration, and, more generally, how the tauopathy is linked to neurodegeneration. Herein, we review what is known about how FTDP-17-linked pathogenic MAPT mutations cause disease, with a major focus on the prion-like properties of wild-type and mutant tau proteins. The hypothesized mechanisms by which mutations in the MAPT gene promote tauopathy are quite varied and may not provide definitive insights into how tauopathy arises in the absence of mutation. Further, differences in the ability of tau and mutant tau proteins to support prion-like propagation in various model systems raise questions about the generalizability of this mechanism in various tauopathies. Notably, understanding the mechanisms of tauopathy induction and spread and tau-induced neurodegeneration has important implications for tau-targeting therapeutics.
Alzheimer's disease: The right drug, the right time Golde, Todd E; DeKosky, Steven T; Galasko, Douglas
Science (American Association for the Advancement of Science),
12/2018, Letnik:
362, Številka:
6420
Journal Article
Recenzirano
Lessons from failed clinical trials can improve the development of Alzheimer's disease–modifying therapies
Alzheimer's disease (AD) is an age-associated neurodegenerative disease that is reaching ...epidemic proportions as a result of the aging of the world's population. Impressive gains in our understanding of AD pathogenesis have not yet translated into disease-modifying therapies that benefit patients. Is this because the knowledge that guides target identification and, hence, therapeutics, is insufficient? Are current clinical trial designs not optimal? Or are other factors contributing? Here, we highlight the challenges of developing effective AD therapies and discuss how lessons learned from failed trials must be implemented to increase the likelihood of success.
Immunoproteostasis is a term used to reflect interactions between the immune system and the proteinopathies that are presumptive “triggers” of many neurodegenerative disorders. The study of ...immunoproteostasis is bolstered by several observations. Mutations or rare variants in genes expressed in microglial cells, known to regulate immune functions, or both can cause, or alter risk for, various neurodegenerative disorders. Additionally, genetic association studies identify numerous loci harboring genes that encode proteins of known immune function that alter risk of developing Alzheimer’s disease (AD) and other neurodegenerative proteinopathies. Further, preclinical studies reveal beneficial effects and liabilities of manipulating immune pathways in various neurodegenerative disease models. Although there are concerns that manipulation of the immune system may cause more harm than good, there is considerable interest in developing immune modulatory therapies for neurodegenerative disorders. Herein, I highlight the promise and challenges of harnessing immunoproteostasis to treat neurodegenerative proteinopathies.
There is increasing evidence that the immune system plays a significant role in many neurodegenerative proteinopathies, especially Alzheimer’s disease. In this Perspective, Golde discusses both the promise and the challenges of immunomodulation in the setting of neurodegenerative disease.
Animal models of adult-onset neurodegenerative diseases have enhanced the understanding of the molecular pathogenesis of Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and ...amyotrophic lateral sclerosis. Nevertheless, our understanding of these disorders and the development of mechanistically designed therapeutics can still benefit from more rigorous use of the models and from generation of animals that more faithfully recapitulate human disease. Here we review the current state of rodent models for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. We discuss the limitations and utility of current models, issues regarding translatability, and future directions for developing animal models of these human disorders.
Anti-inflammatory strategies are proposed to have beneficial effects in Alzheimer’s disease. To explore how anti-inflammatory cytokine signaling affects Aβ pathology, we investigated the effects of ...adeno-associated virus (AAV2/1)-mediated expression of Interleukin (IL)-10 in the brains of APP transgenic mouse models. IL-10 expression resulted in increased Aβ accumulation and impaired memory in APP mice. A focused transcriptome analysis revealed changes consistent with enhanced IL-10 signaling and increased ApoE expression in IL-10-expressing APP mice. ApoE protein was selectively increased in the plaque-associated insoluble cellular fraction, likely because of direct interaction with aggregated Aβ in the IL-10-expressing APP mice. Ex vivo studies also show that IL-10 and ApoE can individually impair glial Aβ phagocytosis. Our observations that IL-10 has an unexpected negative effect on Aβ proteostasis and cognition in APP mouse models demonstrate the complex interplay between innate immunity and proteostasis in neurodegenerative diseases, an interaction we call immunoproteostasis.
•The anti-inflammatory cytokine, IL-10, increases Aβ accumulation in APP mouse brain•IL-10 exacerbates memory impairment in APP mice and reduces synaptic proteins•IL-10 increases ApoE, which, by binding aggregated Aβ, is sequestered in plaques•IL-10 and ApoE suppress microglial Aβ phagocytosis in vitro
Chakrabarty et al. show that Interleukin-10 increases Aβ plaque deposition and impairs cognition in APP mice. This is mechanistically linked to decreased microglial Aβ phagocytosis and increased ApoE expression and sequestration in plaques, consistent with ApoE’s role as a pathological chaperone.
Targeting Notch in oncology: the path forward Majumder, Samarpan; Crabtree, Judy S; Golde, Todd E ...
Nature reviews. Drug discovery,
02/2021, Letnik:
20, Številka:
2
Journal Article
Recenzirano
Notch signalling is involved in many aspects of cancer biology, including angiogenesis, tumour immunity and the maintenance of cancer stem-like cells. In addition, Notch can function as an oncogene ...and a tumour suppressor in different cancers and in different cell populations within the same tumour. Despite promising preclinical results and early-phase clinical trials, the goal of developing safe, effective, tumour-selective Notch-targeting agents for clinical use remains elusive. However, our continually improving understanding of Notch signalling in specific cancers, individual cancer cases and different cell populations, as well as crosstalk between pathways, is aiding the discovery and development of novel investigational Notch-targeted therapeutics.
Adeno-associated virus (AAV) mediated gene expression is a powerful tool for gene therapy and preclinical studies. A comprehensive analysis of CNS cell type tropism, expression levels and ...biodistribution of different capsid serotypes has not yet been undertaken in neonatal rodents. Our previous studies show that intracerebroventricular injection with AAV2/1 on neonatal day P0 results in widespread CNS expression but the biodistribution is limited if injected beyond neonatal day P1. To extend these observations we explored the effect of timing of injection on tropism and biodistribution of six commonly used pseudotyped AAVs delivered in the cerebral ventricles of neonatal mice. We demonstrate that AAV2/8 and 2/9 resulted in the most widespread biodistribution in the brain. Most serotypes showed varying biodistribution depending on the day of injection. Injection on neonatal day P0 resulted in mostly neuronal transduction, whereas administration in later periods of development (24-84 hours postnatal) resulted in more non-neuronal transduction. AAV2/5 showed widespread transduction of astrocytes irrespective of the time of injection. None of the serotypes tested showed any microglial transduction. This study demonstrates that both capsid serotype and timing of injection influence the regional and cell-type distribution of AAV in neonatal rodents, and emphasizes the utility of pseudotyped AAV vectors for translational gene therapy paradigms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Measures from diffusion magnetic resonance imaging reflect changes in the substantia nigra of Parkinson's disease. It is the case, however, that partial volume effects from free water can ...bias diffusion measurements. The bi-tensor diffusion model was introduced to quantify the contribution of free water and eliminates its bias on estimations of tissue microstructure. Here, we test the hypothesis that free water is elevated in the substantia nigra for Parkinson's disease compared with control subjects. This hypothesis was tested between large cohorts of Parkinson's disease and control participants in a single-site study and validated against a multisite study using multiple scanners. The fractional volume of free water was increased in the posterior region of the substantia nigra in Parkinson's disease compared with control subjects in both the single-site and multi-site studies. We did not observe changes in either cohort for free-water–corrected fractional anisotropy or free-water–corrected mean diffusivity. Our findings provide new evidence that the free-water index reflects alteration of the substantia nigra in Parkinson's disease, and this was evidenced across both single-site and multi-site cohorts.
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