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Alzheimer's & Dementia : the Journal of... Mar 2024Neuropathological investigation of presymptomatic or early symptomatic presenilin-1 (PSEN1) mutation carriers in familial Alzheimer's disease (AD) is extremely scarce. (Comparative Study)
Comparative Study
INTRODUCTION
Neuropathological investigation of presymptomatic or early symptomatic presenilin-1 (PSEN1) mutation carriers in familial Alzheimer's disease (AD) is extremely scarce.
METHODS
We report the autopsy findings of brothers with familial AD. Case 1 is a 45-year-old man without obvious cognitive impairment, who committed suicide. Case 2 is a 57-year-old older brother of Case 1 with advanced AD symptoms, who died of hypothermia during wondering.
RESULTS
In both cases, abundant amyloid plaques positive for amyloid β (Aβ) were found throughout the brain. Progression of neuronal loss and increasing amount and extension of neurofibrillary tangle pathology were evident in Case 2. Genetic investigation revealed a PSEN1_p. L392V mutation in both cases.
DISCUSSION
The present study shows a possible neuropathological boundary between symptomatic and preclinical AD with pathogenic PSEN1 mutation. Additional clinicopathological investigation for familial AD-related mutation carriers may be significant to explore the association between familial AD and suicide.
Topics: Humans; Male; Middle Aged; Alzheimer Disease; Amyloid beta-Peptides; Mutation; Presenilin-1; Siblings
PubMed: 38215435
DOI: 10.1002/alz.13675 -
Global Medical Genetics Jan 2024Dementia is a syndrome that can cause a number of progressive illnesses that affect memory, thinking, and ability to perform everyday tasks. Alzheimer's disease (AD) is...
Dementia is a syndrome that can cause a number of progressive illnesses that affect memory, thinking, and ability to perform everyday tasks. Alzheimer's disease (AD) is the most common cause of dementia and represents a major public health problem. AD is a progressive disease, where in early stages there is mild memory loss and in late-stage patient loses the ability to carry on a conversation. AD (for which there is no exact cause and cure known so far) is the sixth leading cause of deaths in the United States. Every 68 second someone develops AD. This study focuses on protein structure modeling of genes presenilin 1 and 2 ( and ) and their mutated forms (Asn141Tyr found in Chinese family, Gly34Ser identified in a Japanese patient, and Arg62Cys & Val214Leu identified in the Korean patients). It also involves wild and mutant type comparison, protein interaction studies, docking and phylogenetic history based on representative ortholog species and also sheds insight into the comparative evolutionary rates of coding sequence across various orthologs. This study gives a time and cost-effective analysis of genes ( and ) underlying AD and genetic alterations that drive development and causes of disease.
PubMed: 38213663
DOI: 10.1055/s-0043-1777849 -
International Journal of Molecular... Jan 2024Presenilin 1 (PS1) is a transmembrane proteolytic subunit of -secretase that cleaves amyloid precursor proteins. Mutations in PS1 (mPS1) are associated with early-onset...
Cultured Rat Hippocampal Neurons Exposed to the Mitochondrial Uncoupler Carbonyl Cyanide Chlorophenylhydrazone Undergo a Rapid, Presenilin-Dependent Change in Neuronal Properties.
Presenilin 1 (PS1) is a transmembrane proteolytic subunit of -secretase that cleaves amyloid precursor proteins. Mutations in PS1 (mPS1) are associated with early-onset familial Alzheimer's disease (AD). The link between mutated PS1, mitochondrial calcium regulation, and AD has been studied extensively in different test systems. Despite the wide-ranging role of mPS1 in AD, there is a paucity of information on the link between PS1 and neuronal cell death, a hallmark of AD. In the present study, we employed the selective mitochondrial uncoupler carbonyl cyanide chlorophenylhydrazone (CCCP) and compared the reactivity of mPS1-transfected cultured rat hippocampal neurons with PS1 and control neurons in a situation of impaired mitochondrial functions. CCCP causes a slow rise in cytosolic and mitochondrial calcium in all three groups of neurons, with the mPS1 neurons demonstrating a faster rise. Consequently, mPS1 neurons were depolarized by CCCP and measured with TMRM, a mitochondrial voltage indicator, more than the other two groups. Morphologically, CCCP produced more filopodia in mPS1 neurons than in the other two groups, which were similarly affected by the drug. Finally, mPS1 transfected neurons tended to die from prolonged exposure to CCCP sooner than the other groups, indicating an increase in vulnerability associated with a lower ability to regulate excess cytosolic calcium.
Topics: Animals; Rats; Calcium; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Cyanides; Neurons; Alzheimer Disease; Calcium, Dietary; Hippocampus; Nitriles
PubMed: 38203751
DOI: 10.3390/ijms25010578 -
International Journal of Molecular... Dec 2023A pathogenic mutation in presenilin-1 (), His214Asn, was found in a male patient with memory decline at the age of 41 in Korea for the first time. The proband patient...
A pathogenic mutation in presenilin-1 (), His214Asn, was found in a male patient with memory decline at the age of 41 in Korea for the first time. The proband patient was associated with a positive family history from his father, paternal aunt, and paternal grandmother without genetic testing. He was diagnosed with early onset Alzheimer's disease (EOAD). His214Asn was initially reported in an Italian family, where the patient developed phenotypes similar to the current proband patient. Magnetic resonance imaging (MRI) scans revealed a mild hippocampal atrophy. The amyloid positron emission tomography (amyloid-PET) was positive, along with the positive test results of the increased amyloid ß (Aβ) oligomerization tendency with blood. The His214 amino acid position plays a significant role in the gamma-secretase function, especially from three additional reported mutations in this residue: His214Asp, His214Tyr, and His214Arg. The structure prediction model revealed that PSEN1 protein His214 may interact with Trp215 of His-Trp cation-π interaction, and the mutations of His214 would destroy this interaction. The His-Trp cation-π interaction between His214 and Trp215 would play a crucial structural role in stabilizing the 4th transmembrane domain of PSEN1 protein, especially when aromatic residues were often reported in the membrane interface of the lipid-extracellular region of alpha helices or beta sheets. The His214Asn would alter the cleavage dynamics of gamma-secretase from the disappeared interactions between His214 and Trp215 inside of the helix, resulting in elevated amyloid production. Hence, the increased Aβ was reflected in the increased Aβ oligomerization tendency and the accumulations of Aβ in the brain from amyloid-PET, leading to EOAD.
Topics: Humans; Male; Histidine; Tryptophan; Alzheimer Disease; Presenilin-1; Amyloid Precursor Protein Secretases; Mutation; Amyloidogenic Proteins; Cations; Republic of Korea
PubMed: 38203287
DOI: 10.3390/ijms25010116 -
The Journal of Biological Chemistry Feb 2024Protein kinase-B (Akt) and the mechanistic target of rapamycin (mTOR) signaling pathways are implicated in Alzheimer's disease (AD) pathology. Akt/mTOR signaling...
Protein kinase-B (Akt) and the mechanistic target of rapamycin (mTOR) signaling pathways are implicated in Alzheimer's disease (AD) pathology. Akt/mTOR signaling pathways, activated by external inputs, enable new protein synthesis at the synapse and synaptic plasticity. The molecular mechanisms impeding new protein synthesis at the synapse in AD pathogenesis remain elusive. Here, we aimed to understand the molecular mechanisms prior to the manifestation of histopathological hallmarks by characterizing Akt1/mTOR signaling cascades and new protein synthesis in the hippocampus of WT and amyloid precursor protein/presenilin-1 (APP/PS1) male mice. Intriguingly, compared to those in WT mice, we found significant decreases in pAkt1, pGSK3β, pmTOR, pS6 ribosomal protein, and p4E-BP1 levels in both post nuclear supernatant and synaptosomes isolated from the hippocampus of one-month-old (presymptomatic) APP/PS1 mice. In synaptoneurosomes prepared from the hippocampus of presymptomatic APP/PS1 mice, activity-dependent protein synthesis at the synapse was impaired and this deficit was sustained in young adults. In hippocampal neurons from C57BL/6 mice, downregulation of Akt1 precluded synaptic activity-dependent protein synthesis at the dendrites but not in the soma. In three-month-old APP/PS1 mice, Akt activator (SC79) administration restored deficits in memory recall and activity-dependent synaptic protein synthesis. C57BL/6 mice administered with an Akt inhibitor (MK2206) resulted in memory recall deficits compared to those treated with vehicle. We conclude that dysregulation of Akt1/mTOR and its downstream signaling molecules in the hippocampus contribute to memory recall deficits and loss of activity-dependent synaptic protein synthesis. In AD mice, however, Akt activation ameliorates deficits in memory recall and activity-dependent synaptic protein synthesis.
Topics: Mice; Male; Animals; Alzheimer Disease; Proto-Oncogene Proteins c-akt; Mice, Transgenic; Mice, Inbred C57BL; Amyloid beta-Protein Precursor; Hippocampus; TOR Serine-Threonine Kinases; Disease Models, Animal; Presenilin-1; Amyloid beta-Peptides
PubMed: 38182004
DOI: 10.1016/j.jbc.2023.105619 -
Journal of Neuroinflammation Jan 2024Widescale evidence points to the involvement of glia and immune pathways in the progression of Alzheimer's disease (AD). AD-associated iPSC-derived glial cells show a...
BACKGROUND
Widescale evidence points to the involvement of glia and immune pathways in the progression of Alzheimer's disease (AD). AD-associated iPSC-derived glial cells show a diverse range of AD-related phenotypic states encompassing cytokine/chemokine release, phagocytosis and morphological profiles, but to date studies are limited to cells derived from PSEN1, APOE and APP mutations or sporadic patients. The aim of the current study was to successfully differentiate iPSC-derived microglia and astrocytes from patients harbouring an AD-causative PSEN2 (N141I) mutation and characterise the inflammatory and morphological profile of these cells.
METHODS
iPSCs from three healthy control individuals and three familial AD patients harbouring a heterozygous PSEN2 (N141I) mutation were used to derive astrocytes and microglia-like cells and cell identity and morphology were characterised through immunofluorescent microscopy. Cellular characterisation involved the stimulation of these cells by LPS and Aβ and analysis of cytokine/chemokine release was conducted through ELISAs and multi-cytokine arrays. The phagocytic capacity of these cells was then indexed by the uptake of fluorescently-labelled fibrillar Aβ.
RESULTS
AD-derived astrocytes and microglia-like cells exhibited an atrophied and less complex morphological appearance than healthy controls. AD-derived astrocytes showed increased basal expression of GFAP, S100β and increased secretion and phagocytosis of Aβ while AD-derived microglia-like cells showed decreased IL-8 secretion compared to healthy controls. Upon immunological challenge AD-derived astrocytes and microglia-like cells showed exaggerated secretion of the pro-inflammatory IL-6, CXCL1, ICAM-1 and IL-8 from astrocytes and IL-18 and MIF from microglia.
CONCLUSION
Our study showed, for the first time, the differentiation and characterisation of iPSC-derived astrocytes and microglia-like cells harbouring a PSEN2 (N141I) mutation. PSEN2 (N141I)-mutant astrocytes and microglia-like cells presented with a 'primed' phenotype characterised by reduced morphological complexity, exaggerated pro-inflammatory cytokine secretion and altered Aβ production and phagocytosis.
Topics: Humans; Astrocytes; Microglia; Induced Pluripotent Stem Cells; Interleukin-8; Alzheimer Disease; Cytokines; Phenotype; Amyloid beta-Peptides; Presenilin-2
PubMed: 38178159
DOI: 10.1186/s12974-023-02951-2 -
Journal of Alzheimer's Disease : JAD 2024Impaired odor identification is a characteristic of sporadic Alzheimer'sdisease(AD), but its presence in autosomal-dominantAD (adAD) remains uncertain.
BACKGROUND
Impaired odor identification is a characteristic of sporadic Alzheimer'sdisease(AD), but its presence in autosomal-dominantAD (adAD) remains uncertain.
OBJECTIVE
To investigate odor identification ability in mutation carriers (MC) and non-carriers (NC) of adAD in relation to years to estimated clinical onset clinical onset (YECO) of disease.
METHODS
Participants from six families with autosomal-dominant mutations (APP Swedish, APP Arctic, and PSEN1 mutations) included 20 MC and 20 NC. The groups were comparable in age, gender, education, number of APOE ɛ4 alleles, and YECO, but differed in global cognition (Mini-Mental State Examination). The MC group included individuals in asymptomatic, symptomatic cognitively unimpaired, mild cognitive impairment, and dementia stages of disease, spanning approximately 40 years of the AD continuum. All NC were asymptomatic. Olfactory function was assessed by means of free and cued identification of common odors summarized as total identification.
RESULTS
MC performed poorer than NC in free and total identification. Four MC and none of the NC were anosmic. Olfactory functions in MC and NC were significantly and inversely related to time course (YECO) for both free and total identification. The decline in free identification began approximately 10 years prior to the estimated clinical onset of AD in MC. Odor identification proficiency was associated with episodic memory and executive function in MC and NC.
CONCLUSIONS
Impaired odor identification is present well before the clinical diagnosis of AD in MC and is associated with disease progression. Odor identification ability may be a useful early biomarker for adAD.
Topics: Humans; Alzheimer Disease; Odorants; Cognitive Dysfunction; Cognition; Mutation; Presenilin-1
PubMed: 38160354
DOI: 10.3233/JAD-230618 -
Journal of Alzheimer's Disease : JAD 2024Chronic disruption of the circadian timing system, often reflected as a loss of restful sleep, also includes myriad other pathophysiological effects.
BACKGROUND
Chronic disruption of the circadian timing system, often reflected as a loss of restful sleep, also includes myriad other pathophysiological effects.
OBJECTIVE
The current study examined how chronic circadian disruption (CD) could contribute to pathology and rate of progression in the AβPP/PS1 mouse model of Alzheimer's disease (AD).
METHODS
A chronic CD was imposed until animals reached 6 or 12 months of age in AβPP/PS1 and C57BL/6J control mice. Home cage activity was monitored for a period of 3-4 weeks prior to the endpoint along with a single timepoint measure of glucose sensitivity. To assess long term effects of CD on the AD phenotype, animals were re-entrained to a no disruption (ND) schedule just prior to the endpoint, after which a Morris water maze (MWM) was used to assess spatial learning and memory.
RESULTS
Dampening of nighttime activity levels occurred in disrupted animals, and female animals demonstrated a greater adaptability to CD. Diminished arginine vasopressin (AVP) and vasoactive intestinal peptide (VIP) levels in the suprachiasmatic nucleus (SCN) of 12-month male AβPP/PS1 exposed to the CD paradigm were observed, potentially accounting for the diminished re-entrainment response. Similarly, CD worsened performance in the MWM in 12-month male AβPP/PS1 animals, whereas no effect was seen in females.
CONCLUSIONS
Collectively, these findings show that exposure to chronic CD impairs circadian behavioral patterns and cognitive phenotypes of AβPP/PS1 mouse model in a sex-dependent manner.
Topics: Mice; Male; Female; Animals; Amyloid beta-Protein Precursor; Mice, Transgenic; Mice, Inbred C57BL; Alzheimer Disease; Disease Models, Animal; Presenilin-1
PubMed: 38143343
DOI: 10.3233/JAD-230089 -
Biomolecules Dec 2023Human neurodegenerative diseases associated with the misfolding of the alpha-synuclein (aS) protein (synucleinopathies) are similar to prion diseases to the extent that...
Human neurodegenerative diseases associated with the misfolding of the alpha-synuclein (aS) protein (synucleinopathies) are similar to prion diseases to the extent that lesions are spread by similar molecular mechanisms. In a transgenic mouse model (M83) overexpressing a mutated (A53T) form of human aS, we had previously found that Protein Misfolding Cyclic Amplification (PMCA) triggered the aggregation of aS, which is associated with a high resistance to the proteinase K (PK) digestion of both human and murine aS, a major hallmark of the disease-associated prion protein. In addition, PMCA was also able to trigger the aggregation of murine aS in C57Bl/6 mouse brains after seeding with sick M83 mouse brains. Here, we show that intracerebral inoculations of M83 mice with C57Bl/6-PMCA samples strikingly shortens the incubation period before the typical paralysis that develops in this transgenic model, demonstrating the pathogenicity of PMCA-aggregated murine aS. In the hind brain regions of these sick M83 mice containing lesions with an accumulation of aS phosphorylated at serine 129, aS also showed a high PK resistance in the N-terminal part of the protein. In contrast to M83 mice, old APPxM83 mice co-expressing human mutated amyloid precursor and presenilin 1 proteins were seen to have an aggregation of aS, especially in the cerebral cortex, hippocampus and striatum, which also contained the highest load of aS phosphorylated at serine 129. This was proven by three techniques: a Western blot analysis of PK-resistant aS; an ELISA detection of aS aggregates; or the identification of aggregates of aS using immunohistochemical analyses of cytoplasmic/neuritic aS deposits. The results obtained with the D37A6 antibody suggest a higher involvement of murine aS in APPxM83 mice than in M83 mice. Our study used novel tools for the molecular study of synucleinopathies, which highlight similarities with the molecular mechanisms involved in prion diseases.
Topics: Animals; Humans; Mice; alpha-Synuclein; Brain; Mice, Transgenic; Peptide Hydrolases; Prion Diseases; Serine; Synucleinopathies
PubMed: 38136658
DOI: 10.3390/biom13121788 -
Extracellular Vesicles and Circulating... 2023Tau propagation, pathogenesis, and neurotoxicity are hallmarks of neurodegenerative diseases that result in cognitive impairment. Tau accumulates in Alzheimer's disease...
Tau propagation, pathogenesis, and neurotoxicity are hallmarks of neurodegenerative diseases that result in cognitive impairment. Tau accumulates in Alzheimer's disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy, and related tauopathies. Knowledge of the mechanisms for tau propagation in neurodegeneration is necessary for understanding the development of dementia. Exosomes, known as extracellular vesicles (EVs), have emerged as participants in promoting tau propagation. Recent findings show that EVs generated by neurons expressing familial mutations of tauopathies of FTDP-17 (P301L and V337M) (mTau) and presenilin (A246E) (mPS1) in AD induce tau propagation and accumulation after injection into rodent brain. To gain knowledge of the proteome cargoes of the mTau and mPS1 EVs that promote tau pathogenesis, this review compares the proteomes of these EVs, which results in important new questions concerning EV mechanisms of tau pathogenesis. Proteomics data show that EVs produced by mTau- and mPS1-expressing iPSC neurons share proteins involved in exocytosis and vesicle secretion and, notably, these EVs also possess differences in protein components of vesicle-mediated transport, extracellular functions, and cell adhesion. It will be important for future studies to gain an understanding of the breadth of familial genetic mutations of tau, presenilin, and other genes in promoting EV initiation of tau propagation and pathogenesis. Furthermore, elucidation of EV cargo components that mediate tau propagation will have potential as biomarkers and therapeutic strategies to ameliorate dementia of tauopathies.
PubMed: 38125374
DOI: 10.20517/evcna.2023.44