scholarly journals Microtubule assembly by soluble tau impairs vesicle endocytosis and excitatory neurotransmission via dynamin sequestration in Alzheimer's disease synapse model

2021 ◽  
Author(s):  
Tetsuya Hori ◽  
Kohgaku Eguchi ◽  
Han-Ying Wang ◽  
Tomohiro Miyasaka ◽  
Laurent Guillaud ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
De Novo ◽  
Microtubule Assembly ◽  
Pleckstrin Homology Domain ◽  
Endocytic Protein ◽  
Brainstem Slices ◽  
Excitatory Neurotransmission ◽  
Synapse Model ◽  
Activity Dependent

Elevation of soluble wild-type (WT) tau occurs in synaptic compartments in Alzheimer's disease. We addressed whether tau elevation affects synaptic transmission at the calyx of Held in brainstem slices. Whole-cell loading of WT human tau (h-tau) in presynaptic terminals at 10-20 μM caused microtubule (MT) assembly and activity-dependent rundown of excitatory neurotransmission. Capacitance measurements revealed that the primary target of WT h-tau is vesicle endocytosis. Blocking MT assembly using nocodazole prevented tau-induced impairments of endocytosis and neurotransmission. Immunofluorescence imaging analyses revealed that MT assembly by WT h-tau loading was associated with an increased bound fraction of the endocytic protein dynamin. A synthetic dodecapeptide corresponding to dynamin-1-pleckstrin-homology domain inhibited MT-dynamin interaction and rescued tau-induced impairments of endocytosis and neurotransmission. We conclude that elevation of presynaptic WT tau induces de novo assembly of MTs, thereby sequestering free dynamins. As a result, endocytosis and subsequent vesicle replenishment are impaired, causing activity-dependent rundown of neurotransmission.

Aminotransferase Levels and Silymarin in de novo Tacrine-Treated Patients with Alzheimer’s Disease

1999 ◽  
Vol 10 (3) ◽  
pp. 181-185 ◽  
Author(s):  
H. Allain ◽  
S. Schück ◽  
S. Lebreton ◽  
A. Strenge-Hesse ◽  
W. Braun ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
De Novo

scholarly journals Intracellular APP Domain Regulates Serine-Palmitoyl-CoA Transferase Expression and Is Affected in Alzheimer's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Marcus O. W. Grimm ◽  
Sven Grösgen ◽  
Tatjana L. Rothhaar ◽  
Verena K. Burg ◽  
Benjamin Hundsdörfer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
De Novo ◽  
Physiological Function ◽  
Proteolytic Processing ◽  
Sphingolipid Metabolism ◽  
Amyloid Beta Peptides ◽  
Beta Peptides ◽  
Coa Transferase ◽  
Key Enzyme

Lipids play an important role as risk or protective factors in Alzheimer's disease (AD), a disease biochemically characterized by the accumulation of amyloid beta peptides (Aβ), released by proteolytic processing of the amyloid precursor protein (APP). Changes in sphingolipid metabolism have been associated to the development of AD. The key enzyme in sphingolipidde novosynthesis is serine-palmitoyl-CoA transferase (SPT). In the present study we identified a new physiological function of APP in sphingolipid synthesis. The APP intracellular domain (AICD) was found to decrease the expression of the SPT subunit SPTLC2, the catalytic subunit of the SPT heterodimer, resulting in that decreased SPT activity. AICD function was dependent on Fe65 and SPTLC2 levels are increased in APP knock-in mice missing a functional AICD domain. SPTLC2 levels are also increased in familial and sporadic ADpostmortembrains, suggesting that SPT is involved in AD pathology.

scholarly journals Difficult case of a rare form of familial Alzheimer’s disease with PSEN1 P117L mutation

2018 ◽  
Vol 11 (1) ◽  
pp. e226664
Author(s):  
Ana Luísa Rocha ◽  
Andreia Costa ◽  
Maria Carolina Garrett ◽  
Joana Meireles
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
De Novo ◽  
Spastic Paraparesis ◽  
Difficult Case ◽  
Diagnostic Challenge ◽  
Subsequent Investigation ◽  
Neurology Clinic ◽  
Upper Limb Paresis

Less than 10% of Alzheimer’s disease (AD) cases are familial. Presenilin-1 (PSEN1) mutations are the most frequent aetiology and may be associated to atypical neurological manifestations. We report the case of a 27-year-old right-handed man, ensuing with mild cognitive impairment, motor discoordination and axial myoclonus after a parachute accident. At age 32 he was referred to our neurology clinic, presenting cognitive impairment, cerebellar syndrome, axial myoclonus and hypomimia, without other signs of parkinsonism. Because of absence of family history, he was worked up along the line of spinal ataxic disorders. Later, he developed pseudobulbar affect, cognitive deterioration, right upper limb paresis and spastic paraparesis. Subsequent investigation identified a PSEN1 P117L mutation and the diagnosis of autosomal dominant AD was made. This case illustrates the diagnostic challenge imposed by atypical presentation of de novo PSEN1 mutation, leading to unnecessary investigation. Genetic study might be essential for defining the diagnosis.

scholarly journals Blood-Borne Activity-Dependent Neuroprotective Protein (ADNP) is Correlated with Premorbid Intelligence, Clinical Stage, and Alzheimer’s Disease Biomarkers

2015 ◽  
Vol 50 (1) ◽  
pp. 249-260 ◽  
Author(s):  
Anna Malishkevich ◽  
Gad A. Marshall ◽  
Aaron P. Schultz ◽  
Reisa A. Sperling ◽  
Judith Aharon-Peretz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Stage ◽  
Disease Biomarkers ◽  
Premorbid Intelligence ◽  
Activity Dependent

scholarly journals The Role of Mitochondrial Dysfunction in the Progression of Alzheimer’s Disease

2019 ◽  
Vol 25 (40) ◽  
pp. 5578-5587 ◽  
Author(s):  
Claus Desler ◽  
Meryl S. Lillenes ◽  
Tone Tønjum ◽  
Lene Juel Rasmussen
Keyword(s):  
Alzheimer’S Disease ◽  
Reactive Oxygen Species ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
De Novo ◽  
Oxygen Species ◽  
De Novo Synthesis ◽  
Atp Production ◽  
Essential Phospholipids

The current molecular understanding of Alzheimer’s disease (AD) has still not resulted in successful interventions. Mitochondrial dysfunction of the AD brain is currently emerging as a hallmark of this disease. One mitochondrial function often affected in AD is oxidative phosphorylation responsible for ATP production, but also for production of reactive oxygen species (ROS) and for the de novo synthesis of pyrimidines. This paper reviews the role of mitochondrial produced ROS and pyrimidines in the aetiology of AD and their proposed role in oxidative degeneration of macromolecules, synthesis of essential phospholipids and maintenance of mitochondrial viability in the AD brain.

scholarly journals Microtubule affinity–regulating kinase 4 with an Alzheimer's disease-related mutation promotes tau accumulation and exacerbates neurodegeneration

2020 ◽  
Vol 295 (50) ◽  
pp. 17138-17147
Author(s):  
Toshiya Oba ◽  
Taro Saito ◽  
Akiko Asada ◽  
Sawako Shimizu ◽  
Koichi M. Iijima ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
De Novo ◽  
Elevated Risk ◽  
Protein Tau ◽  
Function Mechanism ◽  
Total Tau ◽  
Oligomeric Forms

Accumulation of the microtubule-associated protein tau is associated with Alzheimer's disease (AD). In AD brain, tau is abnormally phosphorylated at many sites, and phosphorylation at Ser-262 and Ser-356 plays critical roles in tau accumulation and toxicity. Microtubule affinity–regulating kinase 4 (MARK4) phosphorylates tau at those sites, and a double de novo mutation in the linker region of MARK4, ΔG316E317D, is associated with an elevated risk of AD. However, it remains unclear how this mutation affects phosphorylation, aggregation, and accumulation of tau and tau-induced neurodegeneration. Here, we report that MARK4ΔG316E317D increases the abundance of highly phosphorylated, insoluble tau species and exacerbates neurodegeneration via Ser-262/356–dependent and –independent mechanisms. Using transgenic Drosophila expressing human MARK4 (MARK4wt) or a mutant version of MARK4 (MARK4ΔG316E317D), we found that coexpression of MARK4wt and MARK4ΔG316E317D increased total tau levels and enhanced tau-induced neurodegeneration and that MARK4ΔG316E317D had more potent effects than MARK4wt. Interestingly, the in vitro kinase activities of MARK4wt and MARK4ΔG316E317D were similar. When tau phosphorylation at Ser-262 and Ser-356 was blocked by alanine substitutions, MARK4wt did not promote tau accumulation or exacerbate neurodegeneration, whereas coexpression of MARK4ΔG316E317D did. Both MARK4wt and MARK4ΔG316E317D increased the levels of oligomeric forms of tau; however, only MARK4ΔG316E317D further increased the detergent insolubility of tau in vivo. Together, these findings suggest that MARK4ΔG316E317D increases tau levels and exacerbates tau toxicity via a novel gain-of-function mechanism and that modification in this region of MARK4 may affect disease pathogenesis.

scholarly journals Reply to Peng and Zhao: Loss of endocytic protein TOM1 in Alzheimer’s disease

2020 ◽  
Vol 117 (8) ◽  
pp. 3917-3919
Author(s):  
Alessandra C. Martini ◽  
David Baglietto-Vargas ◽  
Rodrigo Medeiros ◽  
Frank M. LaFerla
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endocytic Protein

scholarly journals Activity-dependent neuroprotector homeobox protein level in Alzheimer's disease in Taiwanese

2012 ◽  
Vol 4 (1-2) ◽  
pp. 48-50 ◽  
Author(s):  
Yu-Fen Lin ◽  
Ming-Hui Yang ◽  
Yuan-Han Yang ◽  
Wen-Cheng Chen ◽  
Chi-Yu Lu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Level ◽  
Homeobox Protein ◽  
Activity Dependent
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