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Current Neurology and Neuroscience... Nov 2022Amyloid beta (Aβ) plaque accumulation is a hallmark pathology contributing to Alzheimer's disease (AD) and is widely hypothesized to lead to cognitive decline. Decades... (Review)
Review
PURPOSE OF REVIEW
Amyloid beta (Aβ) plaque accumulation is a hallmark pathology contributing to Alzheimer's disease (AD) and is widely hypothesized to lead to cognitive decline. Decades of research into anti-Aβ immunotherapies provide evidence for increased Aβ clearance from the brain; however, this is frequently accompanied by complicated vascular deficits. This article reviews the history of anti-Aβ immunotherapies and clinical findings and provides recommendations moving forward.
RECENT FINDINGS
In 20 years of both animal and human studies, anti-Aβ immunotherapies have been a prevalent avenue of reducing hallmark Aβ plaques. In both models and with different anti-Aβ antibody designs, amyloid-related imaging abnormalities (ARIA) indicating severe cerebrovascular compromise have been common and concerning occurrence. ARIA caused by anti-Aβ immunotherapy has been noted since the early 2000s, and the mechanisms driving it are still unknown. Recent approval of aducanumab comes with renewed urgency to consider vascular deficits caused by anti-Aβ immunotherapy.
Topics: Animals; Humans; Amyloid beta-Peptides; Plaque, Amyloid; Alzheimer Disease; Amyloidogenic Proteins; Amyloid; Immunotherapy; Immunologic Factors; Disease Models, Animal
PubMed: 36269539
DOI: 10.1007/s11910-022-01235-1 -
Brain Pathology (Zurich, Switzerland) Jan 2023National Institute on Aging-Alzheimer's Association definition and classification of sporadic Alzheimer's disease (sAD) is based on the assumption that β-amyloid drives... (Review)
Review
National Institute on Aging-Alzheimer's Association definition and classification of sporadic Alzheimer's disease (sAD) is based on the assumption that β-amyloid drives the pathogenesis of sAD, and therefore, β-amyloid pathology is the sine-qua-non condition for the diagnosis of sAD. The neuropathological diagnosis is based on the concurrence of senile plaques (SPs) and neurofibrillary tangles (NFTs) designated as Alzheimer's disease neuropathological changes. However, NFTs develop in the brain decades before the appearance of SPs, and their distribution does not parallel the distribution of SPs. Moreover, NFTs are found in about 85% of individuals at age 65 and around 97% at age 80. SPs occur in 30% at age 65 and 50%-60% at age 80. More than 70 genetic risk factors have been identified in sAD; the encoded proteins modulate cell membranes, synapses, lipid metabolism, and neuroinflammation. Alzheimer's disease (AD) overture provides a new concept and definition of brain aging and sAD for further discussion. AD overture proposes that sAD is: (i) a multifactorial and progressive neurodegenerative biological process, (ii) characterized by the early appearance of 3R + 4Rtau NFTs, (iii) later deposition of β-amyloid and SPs, (iv) with particular non-overlapped regional distribution of NFTs and SPs, (v) preceded by or occurring in parallel with molecular changes affecting cell membranes, cytoskeleton, synapses, lipid and protein metabolism, energy metabolism, neuroinflammation, cell cycle, astrocytes, microglia, and blood vessels; (vi) accompanied by progressive neuron loss and brain atrophy, (vii) prevalent in human brain aging, and (viii) manifested as pre-clinical AD, and progressing not universally to mild cognitive impairment due to AD, and mild, moderate, and severe AD dementia.
Topics: Humans; Aged; Aged, 80 and over; Alzheimer Disease; Neuroinflammatory Diseases; Neurofibrillary Tangles; Amyloid beta-Peptides; Brain; Plaque, Amyloid; tau Proteins
PubMed: 36223647
DOI: 10.1111/bpa.13122 -
Journal of Alzheimer's Disease : JAD 2018Amyloid-β oligomers (AβO) have been proposed as neurotoxins in the synaptic dysfunction that precedes Alzheimer's disease symptoms. Human and animal model studies... (Review)
Review
Amyloid-β oligomers (AβO) have been proposed as neurotoxins in the synaptic dysfunction that precedes Alzheimer's disease symptoms. Human and animal model studies report that senile plaques contain a halo of AβO molecules surrounding these plaques. A far smaller number of oligomers are distributed widely in plaque-free regions. It has been suggested that oligomers migrate from halos to nearby synapses and are incorporated into both pre- and postsynaptic terminals. These two types of oligomers have two different toxicities when extracted and injected in animal models. This paper proposes a shear-energy based explanation for the data in these studies. Shear hypotheses in the preceding three papers in this series are applied to suggest how the hydrodynamics and resulting shear patterns explain the spatial distribution of both AβO types, the apparent synapse loss in the vicinity of plaque particles, and possible reasons for the differing toxicities. A shear-based mechanism is proposed for the preferential migration of locally shear-excited Aβ molecules into the synaptic cleft. It is proposed that high energy laminar shear generated by the forced diversion of interstitial fluid around the flow-impeding plaque particle is responsible for the formation of AβOs around the plaque. It is suggested that in plaque-free regions, a different type of AβO with different toxicity is generated by lower energy shear flow around synapses, depositing AβO within the synapse from either the neuron membrane surface or by prion-like seeding within the synaptic cleft by locally-sheared Aβ molecules near the synapse entry.
Topics: Amyloid; Amyloidosis; Animals; Brain; Humans; Plaque, Amyloid; Shear Strength; Synapses
PubMed: 30223395
DOI: 10.3233/JAD-171080 -
The Indian Journal of Medical Research Jun 2017Alzheimer's disease (AD) is the most common neurodegenerative cortical dementia. It starts with memory loss, spatial disorientation in people above the age of 65 yr with... (Review)
Review
Alzheimer's disease (AD) is the most common neurodegenerative cortical dementia. It starts with memory loss, spatial disorientation in people above the age of 65 yr with a preference to females. Its incidence is expected to increase threefold by 2050. It affects almost one out of ten persons above the age of 65 years. Majority of patients are sporadic, but a very small percentage is autosomal dominant. The pathomechanisms postulated include amyloid cascade hypothesis according to which mutation in amyloid precursor protein causes Aβ aggregation. The next hypothesis is signal transducer and activation of transcription 3 (STAT3) causing aberration in intracellular signalling pathways. Senile plaques and neurofibrillary tangles are other important pathological changes reported. It is observed that dementia research has not yielded the expected result world over, and therefore, the pitfalls with reference to known facts about diagnosis, clinical features, pathogenic mechanisms, assessment of progression, biomarkers, treatment and prevention, as well as brief information on our experiments with relatively inexpensive methods of differentiating the most common types of dementia AD and frontotemporal dementia are discussed.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Brain; Humans; Plaque, Amyloid; Protein Aggregation, Pathological; STAT3 Transcription Factor
PubMed: 29067973
DOI: 10.4103/ijmr.IJMR_74_17 -
The Mount Sinai Journal of Medicine,... 2010Alois Alzheimer first pointed out that the disease which would later bear his name has a distinct and recognizable neuropathological substrate. Since then, much has been... (Review)
Review
Alois Alzheimer first pointed out that the disease which would later bear his name has a distinct and recognizable neuropathological substrate. Since then, much has been added to our understanding of the pathological lesions associated with the condition. The 2 primary cardinal lesions associated with Alzheimer's disease are the neurofibrillary tangle and the senile plaque. The neurofibrillary tangle consists of abnormal accumulations of abnormally phosphorylated tau within the perikaryal cytoplasm of certain neurons. The senile plaque consists of a central core of beta-amyloid, a 4-kD peptide, surrounded by abnormally configured neuronal processes or neurites. Other neuropathological lesions are encountered in cases of Alzheimer's disease, but the disease is defined and recognized by these 2 cardinal lesions. Other lesions include poorly understood changes such as granulovacuolar degeneration and eosinophilic rodlike bodies (Hirano bodies). The loss of synaptic components is a change that clearly has a significant impact on cognitive function and represents another important morphological alteration. It is important to recognize that distinguishing between Alzheimer's disease, especially in its early stages, and normal aging may be very difficult, particularly if one is examining the brains of patients who died at an advanced old age. It is also noted that instances of pure forms of Alzheimer's disease, in the absence of other coexistent brain disease processes, such as infarctions or Parkinson's disease-related lesions, are relatively uncommon, and this must be taken into account by researchers who employ postmortem brain tissues for research.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Brain; Brain Diseases; Humans; Neurofibrillary Tangles; Plaque, Amyloid
PubMed: 20101720
DOI: 10.1002/msj.20157 -
Journal of Neuropathology and... May 2022Senile plaques have been studied in postmortem brains for more than 120 years and the resultant knowledge has not only helped us understand the etiology and...
Senile plaques have been studied in postmortem brains for more than 120 years and the resultant knowledge has not only helped us understand the etiology and pathogenesis of Alzheimer disease (AD), but has also pointed to possible modes of prevention and treatment. Within the last 15 years, it has become possible to image plaques in living subjects. This is arguably the single greatest advance in AD research since the identification of the Aβ peptide as the major plaque constituent. The limitations and potentialities of amyloid imaging are still not completely clear but are perhaps best glimpsed through the perspective gained from the accumulated postmortem histological studies. The basic morphological classification of plaques into neuritic, cored and diffuse has been supplemented by sophisticated immunohistochemical and biochemical analyses and increasingly detailed mapping of plaque brain distribution. Changes in plaque classification and staging have in turn contributed to changes in the definition and diagnostic criteria for AD. All of this information continues to be tested by clinicopathological correlations and it is through the insights thereby gained that we will best be able to employ the powerful tool of amyloid imaging.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Brain; Humans; Plaque, Amyloid
PubMed: 35595841
DOI: 10.1093/jnen/nlac030 -
Molecular Neurodegeneration Jun 2019The Alzheimer's disease (AD) afflicted brain is neuropathologically defined by extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles composed... (Review)
Review
The Alzheimer's disease (AD) afflicted brain is neuropathologically defined by extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau protein. However, accumulating evidence suggests that the presynaptic protein α-synuclein (αSyn), mainly associated with synucleinopathies like Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), is involved in the pathophysiology of AD. Lewy-related pathology (LRP), primarily comprised of αSyn, is present in a majority of autopsied AD brains, and higher levels of αSyn in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) and AD have been linked to cognitive decline. Recent studies also suggest that the asymptomatic accumulation of Aβ plaques is associated with higher CSF αSyn levels in subjects at risk of sporadic AD and in individuals carrying autosomal dominant AD mutations. Experimental evidence has further linked αSyn mainly to tau hyperphosphorylation, but also to the pathological actions of Aβ and the APOEε4 allele, the latter being a major genetic risk factor for both AD and DLB. In this review, we provide a summary of the current evidence proposing an involvement of αSyn either as an active or passive player in the pathophysiological ensemble of AD, and furthermore describe in detail the current knowledge of αSyn structure and inferred function.
Topics: Alzheimer Disease; Brain; Cognitive Dysfunction; Humans; Plaque, Amyloid; alpha-Synuclein; tau Proteins
PubMed: 31186026
DOI: 10.1186/s13024-019-0320-x -
JAMA Neurology Mar 2013Most age-associated neurodegenerative diseases involve the aggregation of specific proteins within the nervous system. In Alzheimer disease, the insidious pathogenic... (Review)
Review
Most age-associated neurodegenerative diseases involve the aggregation of specific proteins within the nervous system. In Alzheimer disease, the insidious pathogenic process begins many years before the symptoms emerge, and the lesions that characterize the disease—senile plaques and neurofibrillary tangles—ramify systematically through the brain. We review evidence that the -amyloid and tau proteins, which aggregate to form senile plaques and neurofibrillary tangles, respectively, are induced to misfold and self-assemble by a process of templated conformational change that amplifies a toxic species. Recent data also indicate that the spread of these lesions from one site to another is mediated by the cellular uptake, transport, and release of endogenous seeds formed by the cognate proteins. This simple pathogenic principle suggests that the formation, trafficking, and metabolism of pathogenic protein seeds are promising therapeutic targets for Alzheimer disease and other neurodegenerative disorders.
Topics: Animals; Humans; Neurodegenerative Diseases; Neurofibrillary Tangles; Plaque, Amyloid; Protein Folding; tau Proteins
PubMed: 23599928
DOI: 10.1001/jamaneurol.2013.1453 -
Molecular Neurodegeneration Jul 2020Alzheimer disease (AD) is the most prominent form of dementia and the 5th leading cause of death in individuals over 65. AD is a complex disease stemming from genetic,... (Review)
Review
Alzheimer disease (AD) is the most prominent form of dementia and the 5th leading cause of death in individuals over 65. AD is a complex disease stemming from genetic, environmental, and lifestyle factors. It is known that AD patients have increased levels of senile plaques, neurofibrillary tangles, and neuroinflammation; however, the mechanism(s) by which the plaques, tangles, and neuroinflammation manifest remain elusive. A recent hypothesis has emerged that resident bacterial populations contribute to the development and progression of AD by contributing to neuroinflammation, senile plaque formation, and potentially neurofibrillary tangle accumulation (Fig. 1). This review will highlight recent studies involved in elucidating microbial involvement in AD development and progression.
Topics: Alzheimer Disease; Amyloid; Brain; Disease Progression; Humans; Neurofibrillary Tangles; Plaque, Amyloid
PubMed: 32709243
DOI: 10.1186/s13024-020-00378-4 -
Frontiers in Bioscience (Landmark... Nov 2022Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized by extracellular senile plaques and the formation of intracellular... (Review)
Review
Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized by extracellular senile plaques and the formation of intracellular neurofibrillary tangles. The accumulation of toxic beta-amyloid (Aβ) induces the overproduction of reactive oxygen species (ROS), nitric oxide (NO) and pro-inflammatory cytokines. Accumulating studies suggest that neuroinflammatory mechanism plays an important role in the occurrence and development of AD. Microglia, astrocytes, macrophages, mast cells and T cells are involved in the pathogenesis of AD through neuroimmune mechanisms and inflammatory reactions. In recent years, many new drugs have been developed for the treatment of AD targeting neuroimmune and inflammatory mechanisms. Although some drugs failed in the Ⅲ phase of clinical trial, they made sense on subsequent research. This paper mainly discusses the positive effects on AD according to immunotherapy, anti-inflammatory treatment and regulation of immune inflammation by traditional Chinese medicine, in order to benefit for prevention or treatment of AD in the future.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Plaque, Amyloid; Microglia; Inflammation
PubMed: 36472107
DOI: 10.31083/j.fbl2711312