scholarly journals Accumulation of saposin in dystrophic neurites is linked to impaired lysosomal functions in Alzheimer’s disease brains

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Md Golam Sharoar ◽  
Sarah Palko ◽  
Yingying Ge ◽  
Takaomi C. Saido ◽  
Riqiang Yan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Amyloid Plaques ◽  
Dystrophic Neurites ◽  
Neuritic Plaques ◽  
Lysosomal Hydrolases ◽  
Aβ Oligomers ◽  
Plaque Growth ◽  
Lysosomal Proteins

AbstractNeuritic plaques in Alzheimer’s disease (AD) brains refer to β-amyloid (Aβ) plaques surrounded by dystrophic neurites (DNs), activated microglia and reactive astrocytes. Most recently, we showed that DNs form sequentially in three layers during plaque growth. Although lysosomal proteins such as LAMP1 are found in DNs, it is not clear how many and how early lysosomal proteins are involved in forming neuritic plaques. To answer this unmet question, we examined APP knock-in (APPNL-G-F), 5xFAD and APP/PS1ΔE9 mouse brains and found that the lysosomal activator proteins saposins (SAPs) and LAMP1 were accumulated to surround Aβ plaques at the earliest stage, namely the 1st layer of DNs. Noticeably, lysosomal hydrolases were not detectable in these early DNs, suggesting that DNs at this early stage likely enrich dysfunctional lysosomes. In old AD mouse brains and in the later stage of human AD brains, SAP-C+-DNs and LAMP1+-DNs were gradually reduced in concomitant with the growth of amyloid plaques. Remarkably, the observed LAMP1 immunoreactivity near plaques in aged AD mouse and human brains were actually associated with disease-associated microglia rather than neuronal sources, likely reflecting more severely impaired lysosomal functions in neurons. Western blot analyses showed increased levels of SAP-C in AD mouse brains, and Aβ oligomers induced elevated levels of SAP-C in cellular assays. The elevated protein levels of SAP-C in AD mouse brains during plaque growth potentially contributed lysosomal membrane leakage and loss of hydrolases. Together, our study indicates that lysosomal functions are impaired by being entrapped in DNs early during plaque growth, and this may viciously facilitate growth of amyloid plaques.

Different Morphology of Neuritic Plaques in the Archicortex of Alzheimer’s Disease with Comorbid Synucleinopathy: A Pilot Study

2020 ◽  
Vol 17 ◽  
Author(s):  
Nikol Jankovska ◽  
Tomas Olejar ◽  
Jaromir Kukal ◽  
Radoslav Matej
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pilot Study ◽  
Time Course ◽  
Clinical Course ◽  
Lewy Bodies ◽  
Dystrophic Neurites ◽  
Neuritic Plaques ◽  
Structural Differences ◽  
Lewy Body Variant

Background: Bulbous neuritic changes in neuritic plaques have already been described, and their possible effect on the clinical course of the disease has been discussed. OBJECTIVE: In our study, we focused on the location and density of these structures in patients with only Alzheimer’s disease (AD) and patients with AD in comorbidity with synucleinopathies. Methods: Utilizing immunohistochemistry and confocal microscopy, we evaluated differences of neocortical and archicortical neuritic plaques and the frequency of bulbous changes in the archicortex of 14 subjects with Alzheimer’s disease (AD), 10 subjects with the Lewy body variant of Alzheimer's disease (AD/DLB), and 4 subjects with Alzheimer's disease with amygdala Lewy bodies (AD/ALB). Also, the progression and density of neuritic changes over the time course of the disease were evaluated. Results: We found structural differences in bulbous dystrophic neurites more often in AD/DLB and AD/ALB than in pure AD cases. The bulbous neuritic changes were more prominent in the initial and progressive phases and were reduced in cases with a long clinical course. Conclusion: Our results indicate that there is a prominent difference in the shape and composition of neocortical and archicortical neuritic plaques and, moreover, that bulbous neuritic changes can be observed at a higher rate in AD/DLB and AD/ALB subjects compared to pure AD subjects. This observation probably reflects that these subacute changes are more easily seen in the faster clinical course of AD patients with comorbidities.

scholarly journals Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease

2020 ◽  
Vol 21 (16) ◽  
pp. 5858 ◽  
Author(s):  
Md. Sahab Uddin ◽  
Md. Tanvir Kabir ◽  
Md. Sohanur Rahman ◽  
Tapan Behl ◽  
Philippe Jeandet ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Clinical Symptoms ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Amyloid Β ◽  
Aβ Oligomers ◽  
Aβ Aggregation ◽  
Clinical Benefits

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of 40–42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised.

Accumulation of cellular prion protein within dystrophic neurites of amyloid plaques in the Alzheimer's disease brain

2010 ◽  
Vol 31 (3) ◽  
pp. 208-214 ◽  
Author(s):  
Reisuke H. Takahashi ◽  
Minoru Tobiume ◽  
Yuko Sato ◽  
Tetsutaro Sata ◽  
Gunnar K. Gouras ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prion Protein ◽  
Amyloid Plaques ◽  
Cellular Prion Protein ◽  
Dystrophic Neurites

A Multifunctional Chemical Agent as an Attenuator of Amyloid and Tau Burden and Neuroinflammation in Alzheimer’s Disease

2019 ◽  
Author(s):  
Hong-Jun Cho ◽  
Anuj K. Sharma ◽  
Ying Zhang ◽  
Michael L. Gross ◽  
Liviu M. Mirica
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Metal Binding ◽  
Amyloid Plaques ◽  
Chemical Agent ◽  
Aβ Oligomers ◽  
Neuroinflammatory Response ◽  
Aβ Aggregation ◽  
5Xfad Mice

<div>Alzheimer’s disease (AD) is the most common neurodegenerative degenerative disease, and its main hallmark is the deposition of amyloid beta (Aβ) peptides. However, several clinical trials focusing on Aβ-targeting agents have failed recently, and thus new therapeutic leads are focusing on alternate targets such as tau protein pathology, Aβ-metal induced oxidative stress, and neuroinflammation. To address these different pathological aspects of AD, we have employed a multifunctional compound (MFC) L1 that integrates Aβ-interacting and metal-binding functional groups in a single molecular framework. By perturbing the interactions between the Aβ species and metal ions during the Aβ aggregation process, L1 alleviates the formation of neurotoxic Aβ oligomers and promotes the formation of nontoxic, amorphous Aβ aggregates. Furthermore, the significant antioxidant activity and strong metal chelating ability of L1 are operating cooperatively to rescue neuroblastoma N2A cells from Cu2+-induced Aβ neurotoxicity. Along with in vivo Aβ-binding and favorable BBB permeability properties, the treatment of transgenic 5xFAD mice with L1 significantly reduces the amount of both amyloid plaques and associated phosphorylated tau (p-tau) aggregates in the brain by 40–50% versus the vehicle-treated 5xFAD mice. Besides, L1 mitigates the neuroinflammatory response of the activated microglia during the Aβ-induced inflammation process. Overall, these results suggest that L1 not only efficiently attenuates the formation of amyloid plaques and p-tau aggregates in vivo, but also reduces the microgliamediated neuroinflammatory response, which is quite uncommon among the previously reported amyloid-targeting chemical agents, and thus L1 could be envisioned as a lead compound for the development of novel AD therapeutics.</div>

99mTc-labeled Small Molecules for Diagnosis of Alzheimer’s Disease: Past, Recent and Future Perspectives

2019 ◽  
Vol 26 (12) ◽  
pp. 2166-2189 ◽  
Author(s):  
Sajjad Molavipordanjani ◽  
Saeed Emami ◽  
Seyed Jalal Hosseinimehr
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Early Stage ◽  
Amyloid Plaques ◽  
Design Synthesis ◽  
Future Studies ◽  
Age Related ◽  
Derivatives Of

Background: Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disease. Its prominent hallmarks are extracellular deposition of β-amyloids (amyloid plaques), intracellular neurofibrillary tangles (NTFs), neurodegeneration and finally loss of cognitive function. Hence, AD diagnosis in the early stage and monitoring of the disease are of great importance. Methods: In this review article, we have reviewed recent efforts for design, synthesis and evaluation of 99mTc labeled small molecule for AD imaging purposes. Results: These small molecules include derivatives of Congo red, benzothiazole, benzofuran, benzoxazole, naphthalene, biphenyl, chalcone, flavone, aurone, stilbene, curcumin, dibenzylideneacetone, quinoxaline, etc. The different aspects of 99mTc-labeled small molecules including chemical structure, their affinity toward amyloid plaques, BBB permeation and in vivo/vitro stability will be discussed. Conclusion: The findings of this review confirm the importance of 99mTc-labeled small molecules for AD imaging. Future studies based on the pharmacophore of these designed compounds are needed for improvement of these molecules for clinical application.

scholarly journals Reduction of Dendritic Inhibition in CA1 Pyramidal Neurons in Amyloidosis Models of Early Alzheimer’s Disease

2020 ◽  
Vol 78 (3) ◽  
pp. 951-964
Author(s):  
Marvin Ruiter ◽  
Lotte J. Herstel ◽  
Corette J. Wierenga
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Action Potentials ◽  
Pyramidal Neurons ◽  
Early Stage ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Excitatory Input ◽  
Aβ Oligomers ◽  
Ca1 Pyramidal Neurons

Background: In an early stage of Alzheimer’s disease (AD), before the formation of amyloid plaques, neuronal network hyperactivity has been reported in both patients and animal models. This suggests an underlying disturbance of the balance between excitation and inhibition. Several studies have highlighted the role of somatic inhibition in early AD, while less is known about dendritic inhibition. Objective: In this study we investigated how inhibitory synaptic currents are affected by elevated Aβ levels. Methods: We performed whole-cell patch clamp recordings of CA1 pyramidal neurons in organotypic hippocampal slice cultures after treatment with Aβ-oligomers and in hippocampal brain slices from AppNL-F-G mice (APP-KI). Results: We found a reduction of spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons in organotypic slices after 24 h Aβ treatment. sIPSCs with slow rise times were reduced, suggesting a specific loss of dendritic inhibitory inputs. As miniature IPSCs and synaptic density were unaffected, these results suggest a decrease in activity-dependent transmission after Aβ treatment. We observed a similar, although weaker, reduction in sIPSCs in CA1 pyramidal neurons from APP-KI mice compared to control. When separated by sex, the strongest reduction in sIPSC frequency was found in slices from male APP-KI mice. Consistent with hyperexcitability in pyramidal cells, dendritically targeting interneurons received slightly more excitatory input. GABAergic action potentials had faster kinetics in APP-KI slices. Conclusion: Our results show that Aβ affects dendritic inhibition via impaired action potential driven release, possibly due to altered kinetics of GABAergic action potentials. Reduced dendritic inhibition may contribute to neuronal hyperactivity in early AD.

Alzheimer's disease: Mismatch between amyloid plaques and neuritic plaques

1989 ◽  
Vol 103 (1) ◽  
pp. 24-28 ◽  
Author(s):  
Heiko Braak ◽  
Eva Braak ◽  
Thomas Ohm ◽  
Jürgen Bohl
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Plaques ◽  
Neuritic Plaques

scholarly journals Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Aβ generation in Alzheimer’s disease

2016 ◽  
Vol 132 (2) ◽  
pp. 235-256 ◽  
Author(s):  
Katherine R. Sadleir ◽  
Patty C. Kandalepas ◽  
Virginie Buggia-Prévot ◽  
Daniel A. Nicholson ◽  
Gopal Thinakaran ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Plaques ◽  
Dystrophic Neurites ◽  
Microtubule Disruption ◽  
Aβ Generation

A Multifunctional Chemical Agent as an Attenuator of Amyloid and Tau Burden and Neuroinflammation in Alzheimer’s Disease

2019 ◽  
Author(s):  
Hong-Jun Cho ◽  
Anuj K. Sharma ◽  
Ying Zhang ◽  
Michael L. Gross ◽  
Liviu M. Mirica
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Metal Binding ◽  
Amyloid Plaques ◽  
Chemical Agent ◽  
Aβ Oligomers ◽  
Neuroinflammatory Response ◽  
Aβ Aggregation ◽  
5Xfad Mice

<div>Alzheimer’s disease (AD) is the most common neurodegenerative degenerative disease, and its main hallmark is the deposition of amyloid beta (Aβ) peptides. However, several clinical trials focusing on Aβ-targeting agents have failed recently, and thus new therapeutic leads are focusing on alternate targets such as tau protein pathology, Aβ-metal induced oxidative stress, and neuroinflammation. To address these different pathological aspects of AD, we have employed a multifunctional compound (MFC) L1 that integrates Aβ-interacting and metal-binding functional groups in a single molecular framework. By perturbing the interactions between the Aβ species and metal ions during the Aβ aggregation process, L1 alleviates the formation of neurotoxic Aβ oligomers and promotes the formation of nontoxic, amorphous Aβ aggregates. Furthermore, the significant antioxidant activity and strong metal chelating ability of L1 are operating cooperatively to rescue neuroblastoma N2A cells from Cu2+-induced Aβ neurotoxicity. Along with in vivo Aβ-binding and favorable BBB permeability properties, the treatment of transgenic 5xFAD mice with L1 significantly reduces the amount of both amyloid plaques and associated phosphorylated tau (p-tau) aggregates in the brain by 40–50% versus the vehicle-treated 5xFAD mice. Besides, L1 mitigates the neuroinflammatory response of the activated microglia during the Aβ-induced inflammation process. Overall, these results suggest that L1 not only efficiently attenuates the formation of amyloid plaques and p-tau aggregates in vivo, but also reduces the microgliamediated neuroinflammatory response, which is quite uncommon among the previously reported amyloid-targeting chemical agents, and thus L1 could be envisioned as a lead compound for the development of novel AD therapeutics.</div>

scholarly journals Associative Interactions among Zinc, Apolipoprotein E, and Amyloid-β in the Amyloid Pathology

2020 ◽  
Vol 21 (3) ◽  
pp. 802 ◽  
Author(s):  
Shin Bi Oh ◽  
Jung Ah Kim ◽  
SuJi Park ◽  
Joo-Yong Lee
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apolipoprotein E ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Aβ Oligomers ◽  
Amyloid Pathology ◽  
Zinc Depletion ◽  
Molecular Sizes ◽  
Tg2576 Mice

Zinc and apolipoprotein E (apoE) are reportedly involved in the pathology of Alzheimer’s disease. To investigate the associative interaction among zinc, apoE, and amyloid-β (Aβ) and its role in amyloid pathogenesis, we performed various biochemical and immunoreactive analyses using brain tissues of Tg2576 mice and synthetic Aβ and apoE peptides. On amyloid plaques or in brain lysates of Tg2576 mice, apoE and Aβ immunoreactivities increased after zinc chelation and were restored by its subsequent replacement. Zinc depletion dissociated apoE/Aβ complexes or larger-molecular sizes of Aβ oligomers/aggregates into smaller-molecular sizes of apoE and/or Aβ monomers/complexes. In the presence of zinc, synthetic apoE and/or Aβ peptides aggregated into larger-molecular sizes of oligomers or complexes. Endogenous proteases or plasmin in brain lysates degraded apoE and/or Aβ complexes, and their proteolytic activity increased with zinc depletion. These biochemical findings suggest that zinc associates with apoE and Aβ to encourage the formation of apoE/Aβ complexes or large aggregates, raising the deposition of zinc-rich amyloid plaques. In turn, the presence of abundant zinc around and within apoE/Aβ complexes may block the access or activity of Aβ-degrading antibodies or proteases. These results support the plausibility of chelation strategy aiming at reducing amyloid pathology in Alzheimer’s disease.

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