Organelle abnormalities in Alzheimer's disease

γ-Secretase complexes containing PS2 are located mainly in late endosomes and lysosomes.

“studies have shown that γ-secretase complexes containing PS2 are primarily localized in late endosomes and lysosomes, which are acidic compartments ideally suited for amyloidogenic processing.”

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PS2 localization in late endosomes and lysosomes is associated with greater intracellular Aβ production.

“The preferential localization of PS2 in late endosomes and lysosomes is particularly significant, as has been associated with a higher level of intracellular Aβ production, a key contributor to amyloid pathology in AD152.”

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Structural and functional impairments in conventional organelles, including mitochondria, endoplasmic reticulum, lysosomes, Golgi apparatus, and peroxisomes, are consistently observed in Alzheimer's disease brains and experimental models.

“Structural and functional impairments in conventional organelles, including mitochondria, endoplasmic reticulum (ER), lysosomes, Golgi apparatus, and peroxisomes, are consistently observed in AD brains and experimental models.”

γ-Secretase complexes containing PS1 have a broader distribution, including early endosomes, the trans-Golgi network, and the plasma membrane.

“In contrast, γ-secretase complexes containing PS1 are more widely distributed, including in early endosomes, TGN, and the plasma membrane152.”

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Pathological protein accumulation within mitochondria contributes to mitochondrial dysfunction and neurodegeneration in Alzheimer's disease.

“Pathological protein accumulation within mitochondria represents another critical mechanism contributing to mitochondrial dysfunction and neurodegeneration in AD.”

Disruptions in the endo-lysosomal system are consistently found in AD.

“Given the established role of the endo-lysosomal network in APP metabolism and Aβ generation, it is not surprising that disruptions in this system are consistently observed in AD.”

Changes in endo-lysosomal function, such as poor acidification, disturbed trafficking, or undigested material buildup, could increase Aβ generation within these compartments.

“This compartment-specific activity suggests that alterations in endo-lysosomal function, such as impaired acidification, disrupted trafficking, or accumulation of undigested material, could disproportionately enhance Aβ generation within these compartments.”

Endo-lysosomal and autophagic organelles take part in APP metabolism.

“The initial indication of the involvement of the endo-lysosome system in AD arises from the participation of multiple organelles within the endo-lysosomal and autophagic networks in the metabolism of APP150,151.”

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Organelle dysfunction is a key contributor to Alzheimer's disease pathogenesis.

“Given these critical roles, organelle dysfunction is increasingly recognized as a key contributor to AD pathogenesis.”

Post-mortem Alzheimer's disease brains consistently show elevated levels of unfolded protein response markers p-eIF2α, PERK, CHOP, and PDI, indicating sustained ER stress.

“Post-mortem studies of AD brains consistently show elevated levels of UPR markers, including phosphorylated eIF2α (p-eIF2α), PERK, CHOP, and PDI, indicating sustained ER stress136–138.”

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Perturbed communication between organelles, such as at mitochondria-associated ER membranes, lipid droplets, and primary cilia, exacerbates signaling imbalances and neuronal vulnerability in Alzheimer's disease.

“Additionally, perturbed communication between organelles, such as at mitochondria-associated ER membranes (MAMs), lipid droplets, and primary cilia, further exacerbates signaling imbalances and neuronal vulnerability.”

Endocytic and lysosomal changes can be detected in the earliest stages of AD.

“Importantly, such endocytic and lysosomal alterations are detectable in the earliest stages of AD.”

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Endosomal pathology may promote increased β-secretase-mediated APP processing, leading to higher Aβ production.

“In vivo studies further support this link, demonstrating that endosomal pathology may promote increased β-secretase–mediated processing of APP, leading to elevated Aβ production158,159.”

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• AssumptionRests on an assumption: Findings from transgenic AD mouse models and cell culture systems can be generalized to human AD pathogenesis.

The appearance of enlarged endosomes coincides in time with the initial increase in Aβ peptide levels.

“The appearance of enlarged endosomes also coincides temporally with the initial rise in Aβ peptide levels156, suggesting a potential causal relationship.”

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In Alzheimer's disease, significant alterations in both endoplasmic reticulum morphology and function have been reported.

“In AD, significant alterations in both ER morphology and function have been reported, underscoring the vulnerability of this organelle to neurodegenerative stress.”

Disruption of mitochondrial calcium homeostasis is an early and prominent feature of Alzheimer's disease, occurring before the appearance of hallmark pathologies.

“Disruption of mitochondrial calcium homeostasis is an early and prominent feature of AD, occurring before the appearance of hallmark pathologies.”

The acidic environment inside the endo-lysosomal system favors the formation of Aβ42 oligomers.

“Additionally, the acidic environment within the endo-lysosomal system favors the formation of Aβ42 oligomers160, which are known to be particularly neurotoxic and trigger tau mis-sorting.”

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Cognitively normal people with neuropathological early-stage AD show endo-lysosomal network dysfunction, especially in regions without local Aβ plaques or tau tangles.

“Even cognitively normal individuals who exhibit neuropathological evidence of early-stage AD show clear signs of endo-lysosomal network dysfunction, particularly in brain regions that have not yet developed local Aβ plaques or tau tangles154.”

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Overexpression of wild-type or mutant tau induces Golgi fragmentation in primary hippocampal neurons.

“Overexpression of wild-type or mutant tau proteins induces Golgi fragmentation in primary hippocampal neurons185, suggesting that tau accumulation and neurofibrillary tangle formation may precede or amplify Golgi disruption during AD progression.”

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Early peroxisomal adaptation is eventually overwhelmed by sustained oxidative burden.

“indicating that early peroxisomal adaptation is eventually overwhelmed by sustained”

In microglia, restoring peroxisomal proteins PMP70, PEX11β, PEX5, and catalase during inflammatory stress improves cellular and behavioral outcomes in AD mouse models.

“In microglia, restoring peroxisomal proteins such as PMP70, PEX11β, PEX5, and catalase during inflammatory stress improves both cellular and behavioral outcomes in AD mouse models205.”

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• AssumptionRests on an assumption: Findings from transgenic AD mouse models and cell culture systems can be generalized to human AD pathogenesis.

Lysosomal glycohydrolases β-galactosidase, β-hexosaminidase, and α-mannosidase show increased activity in skin fibroblasts from symptomatic and presymptomatic familial AD mutation carriers.

“Similarly, lysosomal glycohydrolases including β-galactosidase, β-hexosaminidase, and α-mannosidase show increased activity in skin fibroblasts from both symptomatic and presymptomatic individuals with familial AD mutations163,164.”

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Lysosomal dysfunction is an early event in AD pathogenesis.

“supporting the notion that lysosomal dysfunction is an early event in AD pathogenesis.”

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These enzyme elevations are also seen in the cortex of TgCRND8 mice.

“These enzyme elevations are also observed in the cortex of TgCRND8 mice165.”

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Golgi fragmentation appears to be directly driven by Aβ accumulation, since removing Aβ from the culture medium reverses the effect.

“This fragmentation appears to be directly driven by Aβ accumulation, as the removal of Aβ from the culture medium can reverse the effect, suggesting that Golgi fragmentation is a downstream consequence of amyloid pathology182.”

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Long-term oxidative stress combined with nutrient deprivation caused by extracellular Aβ deposits can promote peroxisomal degradation via autolysis and NBR1-dependent pexophagy.

“Long-term oxidative stress, combined with nutrient deprivation caused by extracellular Aβ deposits, can further promote peroxisomal degradation via autolysis and NBR1-dependent pexophagy198.”

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Alterations in Golgi morphology have been reported in AD.

“Alterations in Golgi morphology have been reported in AD180,181 (Figure 2).”

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Hippocampal DHA levels are significantly decreased.

“Supporting this, elevated VLCFA levels and reduced plasmalogens have been detected in areas with neurofibrillary tangles, while hippocampal DHA levels are significantly decreased196.”

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AD is marked by an increase in the number and size of vesicles linked to degradative pathways.

“In addition to endo-lysosomal abnormalities, AD is marked by a significant increase in both the number and size of vesicles associated with degradative pathways, indicating widespread dysfunction in cellular clearance mechanisms166,167.”

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In transgenic AD mice, peroxisomal proteins PEX14, ABCD3/PMP70, catalase, and SOD2 increase at three months of age but return to baseline by six months.

“For example, in transgenic AD mice, levels of peroxisomal proteins such as PEX14, ABCD3/PMP70, catalase, and SOD2 increase at three months of age but return to baseline by six months199.”

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Expression of mutant APP and PS1, and exposure to synthetic Aβ peptides, causes Golgi fragmentation in neuronal cultures and mouse brains.

“Expression of the mutant APP and PS1, as well as exposure to synthetic Aβ peptides, has been shown to cause Golgi fragmentation in neuronal cultures and mouse brains182.”

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Lysosomal impairment may be an early active contributor to AD pathogenesis rather than only a consequence of degeneration.

“These observations provide further evidence that lysosomal impairment may not be merely a consequence of degeneration, but an early and active contributor to AD pathogenesis.”

Peroxisomes help degrade pro-inflammatory lipid mediators such as prostaglandins and leukotrienes.

“Importantly, peroxisomes help degrade pro-inflammatory lipid mediators such as prostaglandins and leukotrienes206–208.”

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Axonal dystrophy around plaques is evident even in the earliest detectable phases of AD.

“Consistently, axonal dystrophy is evident around plaques even in the earliest detectable phases of AD171.”

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Autophagosomes, amphisomes, and autolysosomes are frequently found within dystrophic neurites surrounding extracellular amyloid plaques.

“Among these, lysosomal-like organelles such as autophagosomes, amphisomes, and autolysosomes are frequently observed within dystrophic neurites that surround extracellular amyloid plaques166,168,169.”

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NPC1 protein is elevated in the hippocampus and cortex of AD patients and APP/PS1 mice.

“For example, the Niemann-Pick type C1 (NPC1) protein, which mediates cholesterol trafficking from lysosomes to other organelles, is elevated in the hippocampus and cortex of AD patients and in APP/PS1 9 mice162.”

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Cathepsin D and β-hexosaminidase A levels are elevated in neurons from AD patients.

“Additionally, cathepsin D and β-hexosaminidase A levels are elevated in neurons from AD patients166.”

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Oligodendrocyte peroxisomes are essential for maintaining axonal integrity by producing lipids and plasmalogens necessary for myelination.

“Oligodendrocyte peroxisomes are essential for maintaining axonal integrity by producing lipids and plasmalogens necessary for myelination203.”

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The relationship between the Golgi and APP metabolism is bidirectional.

“However, the relationship between Golgi and APP metabolism is bidirectional.”

Accumulation of VLCFAs and depletion of DHA and hydroxy-DHA support the transition from peroxisomal adaptation to functional collapse.

“The accumulation of VLCFAs and the depletion of DHA and hydroxy-DHA further support the transition from peroxisomal adaptation to functional collapse201.”

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A progressive decline in peroxisome density has been observed in early affected brain regions such as the entorhinal cortex.

“A progressive decline in peroxisome density has been observed in early affected brain regions such as the entorhinal cortex195, likely reflecting chronic oxidative stress and impaired lipid metabolism.”

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This vesicle accumulation starts early in disease progression, appearing in axons that contact amyloid deposits during initial Aβ pathology.

“This accumulation begins early in disease progression, as these vesicles are found in axons that contact amyloid deposits during the initial stages of Aβ pathology170.”

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Proper Golgi structure is critical for accurate APP trafficking and processing.

“Thus, proper Golgi structure is critical for accurate APP trafficking and processing.”

Loss of oligodendrocyte peroxisomes leads to axonal degeneration, demyelination, and neuroinflammation.

“Their loss leads to axonal degeneration, demyelination, and neuroinflammation204.”

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Lysosomal protein expression and activity are dysregulated in human AD tissue and animal models.

“Complementing these structural and biochemical alterations, multiple studies have reported dysregulation of lysosomal protein expression and activity in both human AD tissue and animal models161, supporting the notion that lysosomal dysfunction”

• cites [161]Not matched

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Some studies report a transient increase in peroxisome abundance during early disease stages, likely reflecting an initial compensatory response to rising ROS.

“Interestingly, some studies report a transient increase in peroxisome abundance during early disease stages, likely reflecting an initial compensatory response to rising ROS.”

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Peroxisomal dysfunction emerges as an early and dynamic pathological event in AD.

“In AD, peroxisomal dysfunction emerges as an early and dynamic pathological event.”

Asymptomatic AD shows significant neuronal hypertrophy, especially profound nucleoli hypertrophy in CA1 neurons of the hippocampus.

“Interestingly, asymptomatic AD has demonstrated significant neuronal hypertrophy, especially profound nucleoli hypertrophy in CA1 neurons of the hippocampus.”

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MAMs act as functional hubs regulating calcium signaling, lipid metabolism, mitochondrial dynamics, autophagy, apoptosis, and inflammation.

“These domains not only act as structural linkages but serve as functional hubs regulating a wide array of cellular processes, including calcium signaling, lipid metabolism, mitochondrial dynamics, autophagy, apoptosis, and inflammation241.”

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Tau hyperphosphorylation and mislocalization from axons to somatodendritic compartments induce nuclear membrane deformation and NPC dysfunction in human stem cell-derived neurons.

“Similarly, tau hyperphosphorylation and its mislocalization from axons to somatodendritic compartments induce nuclear membrane deformation and NPC dysfunction in human stem cell-derived neurons215.”

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Whether lipid droplet accumulation in AD is protective, pathogenic, or both likely depends on context, cell type, and disease stage.

“Whether LD accumulation in AD is protective, pathogenic, or both likely depends on context, cell type, and disease stage.”

The nucleolus acts as a gatekeeper of neuronal stress tolerance.

“Therefore, these data suggest that the nucleolus acts as a gatekeeper of neuronal stress tolerance.”

The extent of lipid accumulation in the choroid plexus correlates with AD neuropathological staging.

“The extent of lipid accumulation in the choroid plexus correlates with AD neuropathological staging, raising the possibility that ApoE-LD-C1q interactions influence disease progression.”

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Compared with ApoE3 or ApoE2, ApoE4-expressing glial cells and hiPSC-derived microglia accumulate significantly more lipid droplets.

“Compared to ApoE3 or ApoE2, ApoE4-expressing glial cells and hiPSC-derived microglia accumulate significantly more LDs231,232.”

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Downregulation of ABCD3/PMP70 may hinder clearance of oxidized lipid species via β-oxidation.

“Downregulation of ABCD3/PMP70 may also hinder the clearance of oxidized lipid species via β-oxidation210.”

• cites [210]Not matched

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Compared with MCI cases with a similar AD pathology load (Braak III-V), this indicates a compensatory mechanism that prevents progression into dementia.

“Compared with MCI cases with a similar load of AD pathology (Braak III-V), this indicates a compensatory mechanism that prevents the disease progression into dementia220,221.”

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The nucleus undergoes profound structural and molecular alterations that contribute to the pathogenesis of neurodegeneration.

“As a central stress response hub, the nucleus undergoes profound structural and molecular alterations that contribute to the pathogenesis of neurodegeneration.”

When peroxisomal function is compromised, these derivatives accumulate and exacerbate inflammation.

“When peroxisomal function is compromised, these derivatives accumulate and exacerbate inflammation209.”

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This early accumulation suggests that lipid droplets may contribute to upstream pathological events in AD.

“This early accumulation suggests LDs may contribute to upstream pathological events in AD.”

Pharmacological reduction of cholesterol esters using statins or by activating CYP46A1 lowers p-tau levels in human neurons.

“Pharmacological reduction of CE using statins or by activating cholesterol 24-hydroxylase (CYP46A1) lowers p-tau levels in human neurons237, suggesting that modifying lipid droplet composition can influence tau pathology.”

• cites [237]Not matched

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The nucleolus is increasingly recognized as a critical stress-sensing organelle in AD.

“Nucleolus, the nuclear substructure responsible for ribosome biogenesis, is also increasingly recognized as a critical stress-sensing organelle in AD.”

Lipid droplet accumulation has been reported in astrocytes of 5xFAD mice.

“Similarly, LD accumulation has been reported in astrocytes of 5xFAD mice234, further supporting a general disruption in lipid metabolism across glial populations.”

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In AD, sustained oxidative stress, protein misfolding, neuroinflammation, and accumulation of neurotoxic molecules such as Aβ oligomers and phosphorylated tau converge on the nucleus, disrupting its integrity and function.

“In AD, sustained oxidative stress, protein misfolding, neuroinflammation, and the accumulation of neurotoxic molecules such as Aβ oligomers and phosphorylated tau, converge on the nucleus, disrupting its integrity and function.”

Lipid droplets serve as regulatory hubs that integrate lipid metabolism with innate immune signaling.

“This suggests LDs serve as regulatory hubs that integrate lipid metabolism with innate immune signaling.”

Mislocalization of transcription factors TDP-43 and ATF2 to the cytoplasm reflects transport dysfunction.

“Mislocalization of key transcription factors like TDP-43 and ATF2 to the cytoplasm further reflects transport dysfunction215.”

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ApoE binds to complement component C1q on lipid droplets, potentially modulating classical complement activation at the CNS-vasculature interface.

“ApoE binds to complement component C1q on LDs, potentially modulating classical complement activation at the CNS–vasculature interface240.”

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Neutral lipid staining in postmortem AD brains revealed abundant lipid droplets in the choroid plexus, particularly in ApoE4 carriers.

“Neutral lipid staining in postmortem AD brains revealed abundant LDs in this region, particularly in ApoE4 carriers240.”

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• AssumptionRests on an assumption: Organelle abnormalities observed in postmortem AD brain tissue reflect antemortem disease processes rather than postmortem or agonal changes.

Advanced AD cases (Braak IV-VI) show marked nucleolar atrophy, paralleling neuronal shrinkage and cell loss.

“In contrast, advanced AD cases (Braak IV–VI) show marked nucleolar atrophy, paralleling neuronal shrinkage and cell loss.”

In microglia, lipid droplet accumulation is associated with a dysfunctional, pro-inflammatory phenotype characteristic of aging and neurodegeneration.

“In microglia, LD accumulation has been associated with a dysfunctional, pro-inflammatory phenotype characteristic of aging and neurodegeneration238.”

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One of the early nuclear pathologies in AD involves disruption of nucleocytoplasmic transport.

“One of the early nuclear pathologies in AD involves the disruption of nucleocytoplasmic transport.”

ApoE4, the strongest genetic risk factor for AD, has been directly linked to enhanced lipid droplet formation.

“The strongest genetic risk factor for AD, Apolipoprotein E4 (ApoE4), has been directly linked to enhanced LD formation.”

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In AD brains, aberrant localization and accumulation of nucleoporins and NPC-associated proteins such as NTF2 and importin α have been reported, particularly in hippocampal CA1 neurons.

“In AD brains, several studies have reported aberrant localization and accumulation of nucleoporins and NPC-associated proteins, such as nuclear transport factor 2 (NTF2) and importin α, particularly in hippocampal CA1 neurons213,214.”

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Modifying lipid droplet composition can influence tau pathology.

“Pharmacological reduction of CE using statins or by activating cholesterol 24-hydroxylase (CYP46A1) lowers p-tau levels in human neurons237, suggesting that modifying lipid droplet composition can influence tau pathology.”

• cites [237]Not matched

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Perturbations in nucleolar function, whether through oxidative damage or impaired rRNA transcription, can activate p53 signaling and trigger slow neuronal degeneration.

“Perturbations in nucleolar function—whether through oxidative damage or impaired rRNA transcription—can activate p53 signaling and trigger slow neuronal degeneration228.”

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Disruption of MAM integrity and function is increasingly recognized as a contributing factor in AD, particularly in relation to mitochondrial dysfunction, calcium dysregulation, aberrant lipid processing, and amyloidogenic APP metabolism.

“Disruption of MAM integrity and function has been increasingly recognized as a contributing factor in AD, particularly in relation to mitochondrial dysfunction, calcium dysregulation, aberrant lipid processing, and amyloidogenic APP metabolism.”

Lipid droplets may modulate AD pathology by influencing tau phosphorylation.

“LDs may also modulate AD pathology by influencing tau phosphorylation.”

In rTg4510 mice, reduction of soluble p-tau and Nup98 restores nucleocytoplasmic transport.

“In rTg4510 mice, reduction of soluble p-tau and Nup98 restores nucleocytoplasmic transport, confirming this mechanistic link216.”

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• AssumptionRests on an assumption: Findings from transgenic AD mouse models and cell culture systems can be generalized to human AD pathogenesis.

Ribosomes isolated from AD hippocampus exhibit increased RNase-sensitive iron and redox activity.

“Consistently, ribosomes isolated from AD hippocampus exhibit increased RNase-sensitive iron and redox activity225.”

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Peroxisomal failure in AD contributes to a complex cascade of lipid imbalance, oxidative stress, and inflammatory dysregulation.

“Taken together, peroxisomal failure in AD contributes to a complex cascade of lipid imbalance, oxidative stress, and inflammatory dysregulation.”

Aβ may affect the seeding ability of exosomal tau.

“Additionally, Aβ may influence the seeding capacity of exosomal tau, indicating possible interplay between the two hallmark pathologies267.”

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Ubiquitinated proteins are present in amyloid plaques and neurofibrillary tangles.

“The involvement of the proteasome in AD was first recognized when ubiquitinated proteins were identified within hallmark lesions, including amyloid plaques and neurofibrillary tangles269–271.”

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CHIP, an E3 ubiquitin ligase, promotes tau ubiquitination and proteasomal degradation.

“The E3 ubiquitin ligase CHIP (carboxy terminus of Hsp70-interacting protein) promotes the ubiquitination and proteasomal degradation of tau276–278.”

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Exosomes transport tau and phosphorylated tau in cerebrospinal fluid and plasma from Alzheimer's disease patients and tau transgenic mice.

“Similarly, exosomes carry tau and phosphorylated tau, as shown in samples from AD patients’ cerebrospinal fluid and plasma, as well as from tau transgenic mice261–263.”

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Oligomeric Aβ40 and Aβ42 directly impair proteasome function in a dose-dependent way by binding and altering the 20S core, blocking substrate degradation.

“Mechanistic studies have demonstrated that oligomeric forms of Aβ40 and Aβ42 directly impair proteasomal function in a dose-dependent manner by binding to and altering the conformation of the 20S core, effectively inhibiting substrate degradation275.”

• Also stated in: § Membraneless organelles (MLOs) · plain

  “Aβ oligomers also impair the proteasome by inducing conformational changes in the 20S core particle, which blocks protein degradation15.”

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Familial AD-linked mutations in PS1 and PS2 exaggerate this calcium flux, contributing to elevated intracellular calcium stores in AD.

“Familial AD-linked mutations in these proteins exaggerate this calcium flux, contributing to the elevated intracellular calcium stores observed in AD250.”

• cites [250]Not matched

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Exosomes from Alzheimer's disease postmortem tissue, mouse models, and neuronal cultures contain full-length APP and its cleavage products.

“Previous studies have detected full-length APP and its cleavage products in exosomes derived from postmortem AD brains, transgenic mouse models, and cultured neurons255–257.”

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Tau degradation is connected to the ubiquitin-proteasome pathway.

“Similarly, the degradation of tau is linked to the ubiquitin-proteasome pathway.”

PS1 and PS2 interact with IP3Rs to regulate ER-to-mitochondria calcium transfer.

“Both PS1 and PS2 interact with inositol 1,4,5-trisphosphate receptors (IP3Rs) to regulate ER-to-mitochondria calcium transfer.”

• cites [250]Not matched

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Blood exosomal tau is elevated even in preclinical Alzheimer's disease.

“Elevated exosomal tau levels in blood have been reported even in preclinical AD stages264, suggesting their potential as early biomarkers.”

• cites [264]Not matched

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Blocking exosome formation or uptake lowers Aβ spread and related neurotoxicity.

“Inhibiting exosome biogenesis or uptake has been shown to reduce both Aβ spread and associated neurotoxicity259,260.”

• cites [259]Not matched

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• cites [260]Not matched

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In vivo, Aβ injection increases heavy polyribosome formation in CA1 pyramidal neuron cytoplasm.

“Additionally, in vivo studies have demonstrated that Aβ injection increases the formation of heavy polyribosomes in the cytoplasm of CA1 pyramidal neurons, a change that may reflect altered translational control during disease progression288.”

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Aβ exposure lowers ribosomal proteins and rRNA in a time- and dose-dependent manner.

“Aβ exposure induces time- and dose-dependent downregulation of ribosomal proteins and rRNA, highlighting its detrimental impact on ribosomal biogenesis and stability120,283.”

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MAMs are important hubs in AD pathogenesis, serving as convergence points for aberrant amyloid processing, calcium dysregulation, and mitochondrial dysfunction.

“Overall, although not yet extensively studied, current findings suggest MAMs as important hubs in AD pathogenesis, serving as convergence points for multiple pathological processes including aberrant amyloid processing, calcium dysregulation, and mitochondrial dysfunction.”

Ribosomal dysfunction is an early and significant event in Alzheimer's disease pathogenesis.

“Ribosomal dysfunction has emerged as an early and significant event in AD pathogenesis16.”

• cites [16]Not matched

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Tau disrupts synthesis of ribosomal proteins and other neuronal proteins such as PSD-95, contributing to synaptic dysfunction.

“Similar to Aβ, tau disrupts the synthesis of ribosomal proteins and other essential neuronal proteins such as PSD-95, further contributing to synaptic dysfunction285–287.”

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Aβ and tau each harm ribosomes via mechanisms that differ yet overlap.

“Both Aβ and tau contribute to ribosomal impairment through distinct but overlapping mechanisms.”

Exosomes are central mediators of intercellular spread of Aβ and tau pathology in Alzheimer's disease.

“These findings suggest exosomes as central mediators of intercellular propagation of Aβ and tau pathology in AD.”

Ribosome-related pathology contributes to impaired protein synthesis and synaptic dysfunction in early neurodegeneration.

“These changes suggest that ribosome-related pathology contributes to impaired protein synthesis and synaptic dysfunction in the early stages of neurodegeneration.”

As disease advances, higher amounts of exosomal Aβ oligomers may drive transfer of toxic species between neurons and worsen pathology.

“However, with disease progression, increased levels of exosomal Aβ oligomers may instead promote neuron-to-neuron transmission of toxic species, exacerbating pathology259.”

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Cofilin activation, especially under oxidative stress, forms actin rods through intermolecular cysteine oxidation.

“Its activation, particularly under oxidative stress, leads to the formation of actin rods through intermolecular cysteine oxidation307.”

• cites [307]Not matched

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The interaction between TIA-1 and tau is enriched in regions with severe tau pathology.

“The interaction between TIA-1 and tau is particularly enriched in regions with severe tau pathology325.”

• cites [325]Not matched

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Widespread organellar changes in Alzheimer's disease reflect a structured breakdown in cellular homeostasis, not a random or uniform disruption.

“The widespread organellar changes in AD collectively reflect a structured breakdown in cellular homeostasis, rather than a random or uniform disruption.”

These changes suggest a complex hierarchical model of dysfunction in which some organelles act as early sensors or effectors and others respond compensatorily or downstream.

“Instead, they suggest a complex hierarchical model of dysfunction where certain organelles may act as early sensors or effectors of pathological processes, while others respond in a compensatory or downstream fashion.”

Spliceosome disruption in Alzheimer's disease likely contributes to transcriptomic instability and aberrant neuronal gene expression.

“Its disruption in AD likely contributes to transcriptomic instability and aberrant neuronal gene expression, reinforcing its emerging role in disease pathogenesis.”

Neurofibrillary tangles made of hyperphosphorylated tau interfere with spliceosome activity.

“Neurofibrillary tangles composed of hyperphosphorylated tau have been shown to interfere with spliceosome activity318.”

• cites [318]Not matched

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In microglia, stressors such as sodium arsenate or Aβ1-42 fibrils induce stress granule formation and sequester SYK, a kinase needed for microglial activation and phagocytosis.

“In microglia, exposure to stressors such as sodium arsenate or Aβ1–42 fibrils induce SG formation and leads to the sequestration of SYK, a kinase essential for microglial activation and phagocytic function.”

Primary cilia dysfunction may contribute to impaired neurogenesis and signaling disturbances characteristic of Alzheimer's disease.

“Overall, these findings suggest that primary cilia play a critical role in maintaining neuronal signaling and plasticity, and that their dysfunction may contribute to the impaired neurogenesis and signaling disturbances characteristic of AD.”

Disrupted splicing, especially involving U1 snRNP, is a consistent molecular feature of Alzheimer's disease.

“Disruption of splicing activity, particularly involving the U1 snRNP complex, has emerged as a consistent molecular feature312.”

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U1 snRNP subunits associate with pathological inclusions, suggesting sequestration and loss of function.

“Specifically, U1 snRNP subunits have been found in association with pathological inclusions, suggesting their sequestration and loss of function313,315,316.”

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Activated cofilin can move to mitochondria and contribute to mitochondrial fragmentation and dysfunction.

“Moreover, activated cofilin can translocate to mitochondria, where it contributes to mitochondrial fragmentation and dysfunction308,309.”

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Elevated cofilin activity is reported in Alzheimer's disease brains and APP transgenic models.

“Elevated cofilin activity has been reported in both AD brains and APP transgenic models305,306.”

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USP10 overexpression induces assembly of tau-containing stress granules even without exogenous stress.

“Similarly, USP10 overexpression induces the assembly of tau-containing SGs even in the absence of exogenous stress, indicating its potent role in modulating SG dynamics and tau pathology327.”

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Under chronic stress or disease perturbations, stress granules may lose liquid-like dynamics and become more stable, less reversible aggregates.

“However, under chronic stress or disease-associated perturbations, SGs may lose their dynamic, liquid-like properties and transition into more stable, less reversible aggregates.”

Organelle dysfunction is part of a coordinated failure in cellular organization, where impairments in one compartment can propagate and worsen vulnerabilities in others.

“Organelle dysfunction should be viewed not as discrete damage, but as part of a coordinated failure in cellular organization, where impairments in one compartment can propagate and exacerbate vulnerabilities in others337.”

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Hirano bodies, intracytoplasmic inclusions in affected neurons, are composed mainly of actin and associated proteins such as tropomyosin, vinculin, α-actinin, ADF, and cofilin.

“Hirano bodies, which are intracytoplasmic inclusions observed in affected neurons, consist primarily of actin along with associated proteins such as tropomyosin, vinculin, α-actinin, actin-depolymerizing factor (ADF), and cofilin300,301.”

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SYK sequestration impairs clearance of Aβ fibrils, worsening amyloid pathology.

“This sequestration impairs the clearance of Aβ fibrils, thereby exacerbating amyloid pathology328.”

• cites [328]Not matched

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Spliceosomal proteins are abnormally deposited in insoluble aggregates isolated from Alzheimer's disease brains.

“These transcriptome-wide defects are accompanied by the abnormal deposition of spliceosomal proteins in insoluble aggregates isolated from AD brains.”

Drosophila models expressing pathogenic tau show extensive RNA splicing errors, including intron retention and activation of non-annotated splice junctions.

“In Drosophila models expressing pathogenic tau, extensive RNA splicing errors have been observed, including retention of introns and activation of non-annotated splice junctions318.”

• cites [318]Not matched

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Mitochondrial dysfunction may initiate metabolic and oxidative stress responses that later affect lysosomal clearance, cytoskeletal transport, and ER stress responses.

“For example, mitochondrial dysfunction may initiate a series of metabolic and oxidative stress responses that subsequently affect lysosomal clearance, cytoskeletal transport, and ER stress responses.”

This pathological transformation of stress granules is implicated in protein inclusions in major neurodegenerative diseases, including Alzheimer's disease.

“Such pathological transformation has been implicated in the formation of protein inclusions in various major neurodegenerative diseases, including AD319,324.”

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• cites [324]Not matched

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TIA-1 and USP10 colocalize with hyperphosphorylated tau in Alzheimer's disease patient brains and tau transgenic mouse models.

“Notably, TIA-1 and USP10 colocalize with hyperphosphorylated tau in the brains of AD patients and tau transgenic mouse models325–327.”

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Actin rods, rod-shaped bundles of ADF/cofilin-actin complexes, are frequently seen in hippocampal and cortical neurites in Alzheimer's disease brains.

“Actin rods, another hallmark feature, are rod-shaped bundles composed of ADF/cofilin-actin complexes that are frequently observed in hippocampal and cortical neurites in AD brains302.”

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Impairments in RNA splicing or stress granule dynamics may precede overt protein aggregation by altering transcriptomic fidelity or proteome balance.

“Similarly, impairments in RNA splicing or stress granule dynamics may precede overt protein aggregation by subtly altering transcriptomic fidelity or proteome balance.”

Nearly all major organelles show functional and structural abnormalities in Alzheimer's disease, in both postmortem human tissue and experimental models.

“As outlined throughout this manuscript, nearly all major organelles exhibit functional and structural abnormalities in AD, both in postmortem human tissue and in experimental models.”

Dysregulation of membraneless organelles in Alzheimer's disease suggests they may act as critical nodes where cellular resilience is compromised.

“Although MLOs are adaptive under normal conditions, their dysregulation in AD, often exacerbated by pathological protein aggregation, suggests that they may act as critical nodes where cellular resilience is compromised.”

In Alzheimer's disease, stress granule-associated proteins are found within amyloid plaques and neurofibrillary tangles.

“In AD, stress granule-associated proteins have been detected within both amyloid plaques and neurofibrillary tangles, implicating SG components in the pathological aggregation of disease-related proteins (Figure 3).”

Proteome and phosphoproteome analyses show altered expression and phosphorylation of splicing regulators and RNA-binding proteins in Alzheimer's disease brain tissue.

“Proteome and phosphoproteome analyses further support these findings, revealing altered expression and phosphorylation of splicing regulators and RNA-binding proteins in AD brain tissues317 (Figure 3).”

• cites [317]Not matched

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In 3xTg-AD mice, primary cilia length is significantly reduced in hippocampal dentate granule cells.

“One study found a significant reduction in primary cilia length in hippocampal dentate granule cells of 3xTg-AD mice333.”

• cites [333]Not matched

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Transcriptomic profiling of postmortem brain tissue from multiple Alzheimer's disease cohorts shows widespread splicing abnormalities, including intron retention, exon skipping, and cryptic splice site use.

“Transcriptomic profiling of postmortem brain tissues from multiple AD cohorts has revealed widespread splicing abnormalities, including intron retention, exon skipping, and the use of cryptic splice sites313,314.”

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