Changes in the ageing brain in health and disease

The brains of individuals, who are cognitively normal, show age–related changes that include an overall reduction in brain volume and weight, which are associated with gyral atrophy and widening of the sulci of the cerebral cortex, and enlargement of the brain ventricles. These changes are partly the result of nerve cell loss but accurate estimates of neuronal loss are notoriously difficult to make. Microscopically, there are increasing amounts of the age–related pigment, lipofuscin, granulovacuolar degeneration in neurons, Hirano bodies, variable amounts of diffuse deposits of β–amyloid in the parenchyma, the presence of neurofibrillary tangles mainly confined to the hippocampus and amygdala, and sparse numbers of senile plaques in these brain regions and also in other cortical areas. Of these changes, neurofibrillary tangles and senile plaques are the neuropathological hallmark of Alzheimer's disease in which they are more abundant and widespread. Alzheimer's disease has therefore been regarded as accelerated brain ageing; however, the realization that there is a strong genetic contribution to developing the disease at least implies that it may not be the inevitable, even if frequent, consequence of old age. Understanding the molecular basis of plaque and tangle formation is advancing greatly and is the main focus of research into the cellular and molecular changes observed in the ageing brain.

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The Triggering Receptor Expressed on Myeloid Cells 2: “TREM-ming” the Inflammatory Component Associated with Alzheimer's Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2013/860959 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 19

Author(s):

Troy T. Rohn

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurofibrillary Tangles ◽

Neurodegenerative Disorder ◽

Late Onset ◽

Senile Plaques ◽

Myeloid Cells ◽

Disease Process ◽

Age Related

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by a progressive loss of memory and cognitive skills. Although much attention has been devoted concerning the contribution of the microscopic lesions, senile plaques, and neurofibrillary tangles to the disease process, inflammation has long been suspected to play a major role in the etiology of AD. Recently, a novel variant in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) has been identified that has refocused the spotlight back onto inflammation as a major contributing factor in AD. Variants in TREM2 triple one's risk of developing late-onset AD. TREM2 is expressed on microglial cells, the resident macrophages in the CNS, and functions to stimulate phagocytosis on one hand and to suppress cytokine production and inflammation on the other hand. The purpose of this paper is to discuss these recent developments including the potential role that TREM2 normally plays and how loss of function may contribute to AD pathogenesis by enhancing oxidative stress and inflammation within the CNS. In this context, an overview of the pathways linking beta-amyloid, neurofibrillary tangles (NFTs), oxidative stress, and inflammation will be discussed.

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Lysosomal Fusion Dysfunction as a Unifying Hypothesis for Alzheimer's Disease Pathology

International Journal of Alzheimer s Disease ◽

10.1155/2012/752894 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 10

Author(s):

Kristen E. Funk ◽

Jeff Kuret

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Disease Progression ◽

Neurofibrillary Tangles ◽

Recent Literature ◽

Senile Plaques ◽

Disease Onset ◽

Granulovacuolar Degeneration

Alzheimer's disease is characterized pathologically by extracellular senile plaques, intracellular neurofibrillary tangles, and granulovacuolar degeneration. It has been debated whether these hallmark lesions are markers or mediators of disease progression, and numerous paradigms have been proposed to explain the appearance of each lesion individually. However, the unfaltering predictability of these lesions suggests a single pathological nidus central to disease onset and progression. One of the earliest pathologies observed in Alzheimer's disease is endocytic dysfunction. Here we review the recent literature of endocytic dysfunction with particular focus on disrupted lysosomal fusion and propose it as a unifying hypothesis for the three most-studied lesions of Alzheimer's disease.

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Synaptic Mitochondria: An Early Target of Amyloid-β and Tau in Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-215139 ◽

2021 ◽

pp. 1-24

Author(s):

Angie K. Torres ◽

Claudia Jara ◽

Han S. Park-Kang ◽

Catalina M. Polanco ◽

Diego Tapia ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mitochondrial Dysfunction ◽

Neurofibrillary Tangles ◽

Senile Plaques ◽

Amyloid Β ◽

Aβ Peptide ◽

Predisposing Factor ◽

Age Related ◽

Synaptic Mitochondria

Alzheimer’s disease (AD) is characterized by cognitive impairment and the presence of neurofibrillary tangles and senile plaques in the brain. Neurofibrillary tangles are composed of hyperphosphorylated tau, while senile plaques are formed by amyloid-β (Aβ) peptide. The amyloid hypothesis proposes that Aβ accumulation is primarily responsible for the neurotoxicity in AD. Multiple Aβ-mediated toxicity mechanisms have been proposed including mitochondrial dysfunction. However, it is unclear if it precedes Aβ accumulation or if is a consequence of it. Aβ promotes mitochondrial failure. However, AβPP could be cleaved in the mitochondria producing Aβ peptide. Mitochondrial-produced Aβ could interact with newly formed ones or with Aβ that enter the mitochondria, which may induce its oligomerization and contribute to further mitochondrial alterations, resulting in a vicious cycle. Another explanation for AD is the tau hypothesis, in which modified tau trigger toxic effects in neurons. Tau induces mitochondrial dysfunction by indirect and apparently by direct mechanisms. In neurons mitochondria are classified as non-synaptic or synaptic according to their localization, where synaptic mitochondrial function is fundamental supporting neurotransmission and hippocampal memory formation. Here, we focus on synaptic mitochondria as a primary target for Aβ toxicity and/or formation, generating toxicity at the synapse and contributing to synaptic and memory impairment in AD. We also hypothesize that phospho-tau accumulates in mitochondria and triggers dysfunction. Finally, we discuss that synaptic mitochondrial dysfunction occur in aging and correlates with age-related memory loss. Therefore, synaptic mitochondrial dysfunction could be a predisposing factor for AD or an early marker of its onset.

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Neuropathology of Aging in Cats and its Similarities to Human Alzheimer’s Disease

Frontiers in Aging ◽

10.3389/fragi.2021.684607 ◽

2021 ◽

Vol 2 ◽

Author(s):

Lorena Sordo ◽

Alessandra C. Martini ◽

E. Fiona Houston ◽

Elizabeth Head ◽

Danièlle Gunn-Moore

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Early Stage ◽

Senile Plaques ◽

Brain Regions ◽

Hyperphosphorylated Tau ◽

Age Related ◽

Cat Brain ◽

Amyloid Aβ ◽

Intraneuronal Aβ

Elderly cats develop age-related behavioral and neuropathological changes that ultimately lead to cognitive dysfunction syndrome (CDS). These neuropathologies share similarities to those seen in the brains of humans with Alzheimer’s disease (AD), including the extracellular accumulation of ß-amyloid (Aβ) and intraneuronal deposits of hyperphosphorylated tau, which are considered to be the two major hallmarks of AD. The present study assessed the presence and distribution of Aβ and tau hyperphosphorylation within the cat brain (n = 55 cats), and how the distribution of these proteins changes with age and the presence of CDS. For this, immunohistochemistry was performed on seven brain regions from cats of various ages, with and without CDS (n = 10 with CDS). Cats accumulate both intracytoplasmic and extracellular deposits of Aβ, as well as intranuclear and intracytoplasmic hyperphosphorylated tau deposits. Large extracellular aggregates of Aβ were found in elderly cats, mainly in the cortical brain areas, with occasional hippocampal aggregates. This may suggest that these aggregates start in cortical areas and later progress to the hippocampus. While Aβ senile plaques in people with AD have a dense core, extracellular Aβ deposits in cats exhibited a diffuse pattern, similar to the early stages of plaque pathogenesis. Intraneuronal Aβ deposits were also observed, occurring predominantly in cortical brain regions of younger cats, while older cats had few to no intraneuronal Aβ deposits, especially when extracellular aggregates were abundant. Intracytoplasmic hyperphosphorylated tau was found within neurons in the brains of elderly cats, particularly in those with CDS. Due to their ultrastructural features, these deposits are considered to be pre-tangles, which are an early stage of the neurofibrillary tangles seen in AD. The largest numbers of pre-tangles are found mainly in the cerebral cortex of elderly cats, whereas lower numbers were found in other regions (i.e., entorhinal cortex and hippocampus). For the first time, intranuclear tau was found in both phosphorylated and non-phosphorylated states within neurons in the cat brain. The highest numbers of intranuclear deposits were found in the cortex of younger cats, and this tended to decrease with age. In contrast, elderly cats with pre-tangles had only occasional or no nuclear labelling.

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NLRP3 Inflammasome: A Starring Role in Amyloid-β- and Tau-Driven Pathological Events in Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-210268 ◽

2021 ◽

pp. 1-22

Author(s):

Mariana Van Zeller ◽

Diogo M. Dias ◽

Ana M. Sebastião ◽

Cláudia A. Valente

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Glial Cells ◽

Neurofibrillary Tangles ◽

Nlrp3 Inflammasome ◽

Neuronal Death ◽

Inflammatory Responses ◽

Senile Plaques ◽

Amyloid Β ◽

Wide Range

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease commonly diagnosed among the elderly population. AD is characterized by the loss of synaptic connections, neuronal death, and progressive cognitive impairment, attributed to the extracellular accumulation of senile plaques, composed by insoluble aggregates of amyloid-β (Aβ) peptides, and to the intraneuronal formation of neurofibrillary tangles shaped by hyperphosphorylated filaments of the microtubule-associated protein tau. However, evidence showed that chronic inflammatory responses, with long-lasting exacerbated release of proinflammatory cytokines by reactive glial cells, contribute to the pathophysiology of the disease. NLRP3 inflammasome (NLRP3), a cytosolic multiprotein complex sensor of a wide range of stimuli, was implicated in multiple neurological diseases, including AD. Herein, we review the most recent findings regarding the involvement of NLRP3 in the pathogenesis of AD. We address the mechanisms of NLRP3 priming and activation in glial cells by Aβ species and the potential role of neurofibrillary tangles and extracellular vesicles in disease progression. Neuronal death by NLRP3-mediated pyroptosis, driven by the interneuronal tau propagation, is also discussed. We present considerable evidence to claim that NLRP3 inhibition, is undoubtfully a potential therapeutic strategy for AD.

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Entropy and Complexity Analyses in Alzheimer’s Disease: An MEG Study

The Open Biomedical Engineering Journal ◽

10.2174/1874120701004010223 ◽

2010 ◽

Vol 4 (1) ◽

pp. 223-235 ◽

Cited By ~ 39

Author(s):

Carlos Gómez ◽

Roberto Hornero

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Fractal Dimension ◽

Background Activity ◽

Senile Plaques ◽

Approximate Entropy ◽

Brain Regions ◽

Brain Disorder ◽

Complexity Measures ◽

Control Subjects

Alzheimer’s disease (AD) is one of the most frequent disorders among elderly population and it is considered the main cause of dementia in western countries. This irreversible brain disorder is characterized by neural loss and the appearance of neurofibrillary tangles and senile plaques. The aim of the present study was the analysis of the magnetoencephalogram (MEG) background activity from AD patients and elderly control subjects. MEG recordings from 36 AD patients and 26 controls were analyzed by means of six entropy and complexity measures: Shannon spectral entropy (SSE), approximate entropy (ApEn), sample entropy (SampEn), Higuchi’s fractal dimension (HFD), Maragos and Sun’s fractal dimension (MSFD), and Lempel-Ziv complexity (LZC). SSE is an irregularity estimator in terms of the flatness of the spectrum, whereas ApEn and SampEn are embbeding entropies that quantify the signal regularity. The complexity measures HFD and MSFD were applied to MEG signals to estimate their fractal dimension. Finally, LZC measures the number of different substrings and the rate of their recurrence along the original time series. Our results show that MEG recordings are less complex and more regular in AD patients than in control subjects. Significant differences between both groups were found in several brain regions using all these methods, with the exception of MSFD (p-value < 0.05, Welch’s t-test with Bonferroni’s correction). Using receiver operating characteristic curves with a leave-one-out cross-validation procedure, the highest accuracy was achieved with SSE: 77.42%. We conclude that entropy and complexity analyses from MEG background activity could be useful to help in AD diagnosis.

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Emerging Link between Alzheimer’s Disease and Homeostatic Synaptic Plasticity

Neural Plasticity ◽

10.1155/2016/7969272 ◽

2016 ◽

Vol 2016 ◽

pp. 1-19 ◽

Cited By ~ 29

Author(s):

Sung-Soo Jang ◽

Hee Jung Chung

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Plasticity ◽

Senile Plaques ◽

Long Term Potentiation ◽

Brain Regions ◽

Synaptic Activity ◽

Homeostatic Plasticity ◽

Brain Disorder

Alzheimer’s disease (AD) is an irreversible brain disorder characterized by progressive cognitive decline and neurodegeneration of brain regions that are crucial for learning and memory. Although intracellular neurofibrillary tangles and extracellular senile plaques, composed of insoluble amyloid-β(Aβ) peptides, have been the hallmarks of postmortem AD brains, memory impairment in early AD correlates better with pathological accumulation of soluble Aβoligomers and persistent weakening of excitatory synaptic strength, which is demonstrated by inhibition of long-term potentiation, enhancement of long-term depression, and loss of synapses. However, current, approved interventions aiming to reduce Aβlevels have failed to retard disease progression; this has led to a pressing need to identify and target alternative pathogenic mechanisms of AD. Recently, it has been suggested that the disruption of Hebbian synaptic plasticity in AD is due to aberrant metaplasticity, which is a form of homeostatic plasticity that tunes the magnitude and direction of future synaptic plasticity based on previous neuronal or synaptic activity. This review examines emerging evidence for aberrant metaplasticity in AD. Putative mechanisms underlying aberrant metaplasticity in AD will also be discussed. We hope this review inspires future studies to test the extent to which these mechanisms contribute to the etiology of AD and offer therapeutic targets.

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