Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease

Acta Neuropathologica, Год журнала: 2020, Номер 140(6), С. 793 - 810

Опубликована: Авг. 31, 2020

Abstract Therapies targeting late events in Alzheimer’s disease (AD), including aggregation of amyloid beta (Aβ) and hyperphosphorylated tau, have largely failed, probably because they are given after significant neuronal damage has occurred. Biomarkers suggest that the earliest event AD is a decrease cerebral blood flow (CBF). This caused by constriction capillaries contractile pericytes, evoked oligomeric Aβ. CBF also reduced neutrophil trapping clot formation, perhaps secondary to capillary constriction. The fall potentiates neurodegeneration upregulating BACE1 enzyme makes Aβ promoting tau hyperphosphorylation. Surprisingly, therefore, reduction may play crucial role driving cognitive decline initiating cascade itself, or being amplifying production. Here, we review developments this area neglected current approaches AD, with aim novel mechanism-based therapeutic approaches.

Язык: Английский

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Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain

EBioMedicine, Год журнала: 2020, Номер 58, С. 102919 - 102919

Опубликована: Июль 31, 2020

BackgroundMicroglia, the brain's principal immune cell, are increasingly implicated in Alzheimer's disease (AD), but molecular interfaces through which these cells contribute to amyloid beta (Aβ)-related neurodegeneration unclear. We recently identified microglial contributions homeostatic and disease-associated modulation of perineuronal nets (PNNs), extracellular matrix structures that enwrap stabilize neuronal synapses, whether PNNs altered AD remains controversial.MethodsExtensive histological analysis was performed on male female 5xFAD mice at 4, 8, 12, 18 months age assess plaque burden, microgliosis, PNNs. Findings were validated postmortem tissue. The role neuroinflammation PNN loss investigated via LPS treatment, ability prevent or rescue disease-related reductions assessed by treating 3xTg-AD model with colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 deplete microglia.FindingsUtilizing mouse human cortical tissue, we report extensively lost proportion burden. Activated microglia closely associate engulf damaged brain, inclusions material evident microglia, while aggrecan, a critical component, deposits within dense-core plaques. Disease-associated parvalbumin (PV)+ interneurons, frequently coated PNNs, preceded coverage integrity impairments, similar phenotypes elicited wild-type following activation LPS. Chronic pharmacological depletion prevents loss, results observed aged mice, this occurs despite persistence.InterpretationWe conclude phenotypically facilitate plaque-dependent brain.FundingThe NIH (NIA, NINDS) Association.

Язык: Английский

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GABAergic Inhibitory Interneuron Deficits in Alzheimer’s Disease: Implications for Treatment

Frontiers in Neuroscience, Год журнала: 2020, Номер 14

Опубликована: Июнь 30, 2020

Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by severe cognitive deficits and pathologically amyloid plaques, neuronal loss, neurofibrillary tangles. Abnormal β-protein (Aβ) deposition in the brain often thought of as major initiating factor AD neuropathology. However, gamma-aminobutyric acid (GABA) inhibitory interneurons are resistant to Aβ deposition, decreases synaptic glutamatergic transmission decrease neural network activity. Furthermore, there now evidence suggesting that activity aberrantly increased patients animal models due functional decreased GABA interneurons, contributing deficits. Here we describe roles played excitatory neurons Aβ-induced how altered regulate We also comprehensively review recent studies on receptors can be exploited for therapeutic benefit. an emerging target AD, with further clinical trials urgently warranted.

Язык: Английский

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Neuronal excitation/inhibition imbalance: core element of a translational perspective on Alzheimer pathophysiology

Ageing Research Reviews, Год журнала: 2021, Номер 69, С. 101372 - 101372

Опубликована: Май 21, 2021

Our incomplete understanding of the link between Alzheimer's Disease pathology and symptomatology is a crucial obstacle for therapeutic success. Recently, translational studies have begun to connect dots protein alterations deposition, brain network dysfunction cognitive deficits. Disturbance neuronal activity, in particular an imbalance underlying excitation/inhibition (E/I), appears early AD, can be regarded as forming central structural dysfunction. While there are emerging (non-)pharmacological options influence this imbalance, complexity human dynamics has hindered identification optimal approach. We suggest that focusing on integration neurophysiological aspects AD at micro-, meso- macroscale, with support computational modeling, unite fundamental clinical knowledge, provide general framework, rational targets.

Язык: Английский

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Reactive astrocytes: The nexus of pathological and clinical hallmarks of Alzheimer’s disease

Ageing Research Reviews, Год журнала: 2021, Номер 68, С. 101335 - 101335

Опубликована: Апрель 1, 2021

Astrocyte reactivity is a hallmark of neuroinflammation that arises with Alzheimer's disease (AD) and nearly every other neurodegenerative condition. While astrocytes certainly contribute to classic inflammatory processes (e.g. cytokine release, waste clearance, tissue repair), newly emerging technologies for measuring targeting cell specific activities in the brain have uncovered essential roles synapse function, metabolism, neurovascular coupling, sleep/wake patterns. In this review, we use holistic approach incorporate, expand upon, neuroinflammatory concepts consider how astrocyte dysfunction/reactivity modulates multiple pathological clinical hallmarks AD. Our ever-evolving understanding signaling neurodegeneration not only revealing new drug targets treatments dementia but suggesting reimagine AD pathophysiological mechanisms.

Язык: Английский

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Microglia as hackers of the matrix: sculpting synapses and the extracellular space

Cellular and Molecular Immunology, Год журнала: 2021, Номер 18(11), С. 2472 - 2488

Опубликована: Авг. 19, 2021

Abstract Microglia shape the synaptic environment in health and disease, but synapses do not exist a vacuum. Instead, pre- postsynaptic terminals are surrounded by extracellular matrix (ECM), which together with glia comprise four elements of contemporary tetrapartite synapse model. While research this area is still just beginning, accumulating evidence points toward novel role for microglia regulating ECM during normal brain homeostasis, such processes may, turn, become dysfunctional disease. As it relates to synapses, reported modify perisynaptic matrix, diffuse that surrounds dendritic axonal terminals, as well perineuronal nets (PNNs), specialized reticular formations compact enwrap neuronal subsets stabilize proximal synapses. The interconnected relationship between they embedded suggests alterations one structure necessarily affect dynamics other, may need sculpt within. Here, we provide an overview microglial regulation PNNs, propose candidate mechanisms these structures be modified, present implications modifications homeostasis

Язык: Английский

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Alzheimer’s disease as a synaptopathy: Evidence for dysfunction of synapses during disease progression

Frontiers in Synaptic Neuroscience, Год журнала: 2023, Номер 15

Опубликована: Март 9, 2023

The synapse has consistently been considered a vulnerable and critical target within Alzheimer’s disease, loss is, to date, one of the main biological correlates cognitive decline disease. This occurs prior neuronal with ample evidence that synaptic dysfunction precedes this, in support idea failure is crucial stage disease pathogenesis. two pathological hallmarks abnormal aggregates amyloid or tau proteins, have had demonstrable effects on physiology animal cellular models There also growing these proteins may synergistic effect neurophysiological dysfunction. Here, we review some findings alterations what know from models. First, briefly summarize human suggest synapses are altered, including how this relates network activity. Subsequently, considered, highlighting mouse pathology role play dysfunction, either isolation examining pathologies interact specifically focuses function observed models, typically measured using electrophysiology calcium imaging. Following loss, it would be impossible imagine not alter oscillatory activity brain. Therefore, discusses underpin aberrant patterns seen patients. Finally, an overview key directions considerations field covered. includes current therapeutics targeted at but methods modulate rescue patterns. Other important future avenues note include non-neuronal cell types such as astrocytes microglia, mechanisms independent will certainly continue for foreseeable future.

Язык: Английский

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Fast-spiking parvalbumin-positive interneurons in brain physiology and Alzheimer’s disease

Molecular Psychiatry, Год журнала: 2023, Номер 28(12), С. 4954 - 4967

Опубликована: Июль 7, 2023

Abstract Fast-spiking parvalbumin (PV) interneurons are inhibitory with unique morphological and functional properties that allow them to precisely control local circuitry, brain networks memory processing. Since the discovery in 1987 PV is expressed a subset of fast-spiking GABAergic neurons, our knowledge complex molecular physiological these cells has been expanding. In this review, we highlight specific neurons fire at high frequency reliability, enabling network oscillations shape encoding, consolidation retrieval memories. We next discuss multiple studies reporting neuron impairment as critical step neuronal dysfunction cognitive decline mouse models Alzheimer’s disease (AD). Finally, propose potential mechanisms underlying AD argue early changes activity could be causal AD-associated significant contributor pathogenesis.

Язык: Английский

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Epilepsy and epileptiform activity in late-onset Alzheimer disease: clinical and pathophysiological advances, gaps and conundrums

Nature Reviews Neurology, Год журнала: 2024, Номер 20(3), С. 162 - 182

Опубликована: Фев. 14, 2024

Язык: Английский

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The concept of resilience to Alzheimer’s Disease: current definitions and cellular and molecular mechanisms

Molecular Neurodegeneration, Год журнала: 2024, Номер 19(1)

Опубликована: Апрель 8, 2024

Abstract Some individuals are able to maintain their cognitive abilities despite the presence of significant Alzheimer’s Disease (AD) neuropathological changes. This discrepancy between cognition and pathology has been labeled as resilience evolved into a widely debated concept. External factors such stimulation associated with AD, but exact cellular molecular underpinnings not completely understood. In this review, we discuss current definitions used in field, highlight translational approaches investigate AD summarize underlying substrates that have derived from human animal studies, which received more attention last few years. From these studies picture emerges resilient different patients terms specific pathological species reaction pathology, possibly helps up certain tipping point. Studying rare can be great importance it could pave way novel therapeutic avenues for AD.

Язык: Английский

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