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Increased neuronal expression of the early endosomal adaptor APPL1 replicates Alzheimer's Disease-related endosomal and synaptic dysfunction with cholinergic neurodegeneration
Jiang, Ying; Sachdeva, Kuldeep; Goulbourne, Chris N; Berg, Martin J; Peddy, James; Stavrides, Philip H; Pensalfini, Anna; Pawlik, Monika; Malampati, Sandeep; Whyte, Lauren; Basavarajappa, Balapal S; Shivakumar, Subbanna; Bleiwas, Cynthia; Smiley, John F; Mathews, Paul M; Nixon, Ralph A
Endosomal system dysfunction within neurons is a prominent early feature of Alzheimer's disease (AD) pathology. Multiple AD risk factors are regulators of endocytosis and are known to cause hyper-activity of the early-endosome small GTPase rab5, resulting in neuronal endosomal pathway disruption and cholinergic neurodegeneration. Adaptor protein containing Pleckstrin homology domain, Phosphotyrosine binding domain, Leucine zipper motif (APPL1), an important rab5 effector protein and signaling molecule, has been shown in vitro to interface between endosomal and neuronal dysfunction through a rab5-activating interaction with the BACE1-generated C-terminal fragment of amyloid precursor protein (APP-βCTF), a pathogenic APP fragment generated within endosomal compartments. To understand the contribution of APPL1 to AD-related endosomal dysfunction in vivo, we generated a transgenic mouse model over-expressing human APPL1 within neurons (Thy1-APPL1). Strongly supporting the important endosomal regulatory roles of APPL1 and their relevance to AD etiology, Thy1-APPL1 mice (both sexes) develop enlarged neuronal early endosomes and increased synaptic endocytosis due to increased rab5 activation. We demonstrated pathophysiological consequences of APPL1 overexpression, including functional changes in hippocampal long-term potentiation (LTP) and long-term depression (LTD), degeneration of large projection cholinergic neurons of the basal forebrain, and impaired hippocampal-dependent memory. Our evidence shows that neuronal APPL1 elevation modeling its functional increase in the AD brain induces a cascade of AD-related pathological effects within neurons, including early endosome anomalies, synaptic dysfunction, and selective neurodegeneration. Our in vivo model highlights the contributions of APPL1 to the pathobiology and neuronal consequences of early endosomal pathway disruption and its potential value as a therapeutic target.Significance Statement Neuronal endosome dysfunction appears early in Alzheimer's disease (AD) and is linked to memory loss. Genes and risk factors associated with AD often increase rab5 activity, a protein that disrupts endosomal signalling when hyperactivated. APPL1, a key rab5 partner, worsens this dysfunction via its interaction with APP-βCTF, a protein fragment associated with AD. To explore APPL1's role, we created a genetically modified mouse that overexpresses APPL1 in neurons. This model provides the first in vivo evidence that APPL1 overexpression triggers key AD-like effects: rab5 hyperactivation, enlarged early endosomes, loss of cholinergic neurons, reduced synaptic plasticity in memory-related brain regions, and memory deficits. These findings highlight APPL1's role in AD pathogenesis and its potential as a therapeutic target.
PMID: 40514243
ISSN: 1529-2401
CID: 5869952
Increased neuronal expression of the early endosomal adaptor APPL1 replicates Alzheimer's Disease-related endosomal and synaptic dysfunction with cholinergic neurodegeneration
Jiang, Ying; Sachdeva, Kuldeep; Goulbourne, Chris N; Berg, Martin J; Peddy, James; Stavrides, Philip H; Pensalfini, Anna; Pawlik, Monika; Malampati, Sandeep; Whyte, Lauren; Basavarajappa, Balapal S; Shivakumar, Subbanna; Bleiwas, Cynthia; Smiley, John F; Mathews, Paul M; Nixon, Ralph A
Endosomal system dysfunction within neurons is a prominent early feature of Alzheimer's disease (AD) pathology. Multiple AD risk factors are regulators of endocytosis and are known to cause hyper-activity of the early-endosome small GTPase rab5, resulting in neuronal endosomal pathway disruption and cholinergic neurodegeneration. Adaptor protein containing Pleckstrin homology domain, Phosphotyrosine binding domain, Leucine zipper motif (APPL1), an important rab5 effector protein and signaling molecule, has been shown in vitro to interface between endosomal and neuronal dysfunction through a rab5-activating interaction with the BACE1-generated C-terminal fragment of amyloid precursor protein (APP-βCTF), a pathogenic APP fragment generated within endosomal compartments. To understand the contribution of APPL1 to AD-related endosomal dysfunction in vivo, we generated a transgenic mouse model over-expressing human APPL1 within neurons (Thy1-APPL1). Strongly supporting the important endosomal regulatory roles of APPL1 and their relevance to AD etiology, Thy1-APPL1 mice (both sexes) develop enlarged neuronal early endosomes and increased synaptic endocytosis due to increased rab5 activation. We demonstrated pathophysiological consequences of APPL1 overexpression, including functional changes in hippocampal long-term potentiation (LTP) and long-term depression (LTD), degeneration of large projection cholinergic neurons of the basal forebrain, and impaired hippocampal-dependent memory. Our evidence shows that neuronal APPL1 elevation modeling its functional increase in the AD brain induces a cascade of AD-related pathological effects within neurons, including early endosome anomalies, synaptic dysfunction, and selective neurodegeneration. Our in vivo model highlights the contributions of APPL1 to the pathobiology and neuronal consequences of early endosomal pathway disruption and its potential value as a therapeutic target.Significance Statement Neuronal endosome dysfunction appears early in Alzheimer's disease (AD) and is linked to memory loss. Genes and risk factors associated with AD often increase rab5 activity, a protein that disrupts endosomal signalling when hyperactivated. APPL1, a key rab5 partner, worsens this dysfunction via its interaction with APP-βCTF, a protein fragment associated with AD. To explore APPL1's role, we created a genetically modified mouse that overexpresses APPL1 in neurons. This model provides the first in vivo evidence that APPL1 overexpression triggers key AD-like effects: rab5 hyperactivation, enlarged early endosomes, loss of cholinergic neurons, reduced synaptic plasticity in memory-related brain regions, and memory deficits. These findings highlight APPL1's role in AD pathogenesis and its potential as a therapeutic target.
PMID: 40514243
ISSN: 1529-2401
CID: 5869942
Increased neuronal expression of the early endosomal adaptor APPL1 leads to endosomal and synaptic dysfunction with cholinergic neurodegeneration
Jiang, Ying; Sachdeva, Kuldeep; Goulbourne, Chris N; Berg, Martin J; Peddy, James; Stavrides, Philip H; Pensalfini, Anna; Pawlik, Monika; Whyte, Lauren; Balapal, Basavaraj S; Shivakumar, Subbanna; Bleiwas, Cynthia; Smiley, John F; Mathews, Paul M; Nixon, Ralph A
UNLABELLED:Dysfunction of the endolysosomal system within neurons is a prominent feature of Alzheimer's disease (AD) pathology. Multiple AD-risk factors are known to cause hyper-activity of the early-endosome small GTPase rab5, resulting in neuronal endosomal pathway disruption. APPL1, an important rab5 effector protein, is an interface between endosomal and neuronal function through a rab5-activating interaction with the BACE1-generated C-terminal fragment (βCTF or C99) of the amyloid precursor protein (APP), a pathogenic APP fragment generated within endolysosomal compartments. To better understand the role of APPL1 in the AD endosomal phenotype, we generated a transgenic mouse model over-expressing human APPL1 within neurons (Thy1-APPL1 mice). Consistent with the important endosomal regulatory role of APPL1, Thy1-APPL1 mice have enlarged neuronal early endosomes and increased synaptic endocytosis due to increased rab5 activation. We additionally demonstrate pathological consequences of APPL1 overexpression, including functional changes in hippocampal long-term potentiation (LTP) and long-term depression (LTD), as well as degeneration of the large projection cholinergic neurons of the basal forebrain and impairment of hippocampal-dependent memory. Our findings show that increased neuronal APPL1 levels lead to a cascade of pathological effects within neurons, including early endosomal alterations, synaptic dysfunction, and neurodegeneration. Multiple risk factors and molecular regulators, including APPL1 activity, are known to contribute to the endosomal dysregulation seen in the early stages of AD, and these findings further highlight the shared pathobiology and consequences to a neuron of early endosomal pathway disruption. SIGNIFICANCE STATEMENT/UNASSIGNED:Dysfunction in the endolysosomal system within neurons is a key feature of Alzheimer's disease (AD). Multiple AD risk factors lead to hyperactivity of the early-endosome GTPase rab5, disrupting neuronal pathways including the cholinergic circuits involved early in memory decline. APPL1, a crucial rab5 effector, connects endosomal and neuronal functions through its interaction with a specific amyloid precursor protein (APP) fragment generated within endosomes. To understand APPL1's role, a transgenic mouse model over-expressing human APPL1 in neurons (Thy1-APPL1 mice) was developed. These mice show enlarged early endosomes and increased synaptic endocytosis due to rab5 activation, resulting in impaired hippocampal long-term potentiation and depression, the degeneration of basal forebrain cholinergic neurons, and memory deficits, highlighting a pathological cascade mediated through APPL1 at the early endosome.
PMCID:11430014
PMID: 39345644
ISSN: 2692-8205
CID: 5845182
Apolipoprotein E2 Expression Alters Endosomal Pathways in a Mouse Model With Increased Brain Exosome Levels During Aging
Peng, Katherine Y; Liemisa, Braison; Pasato, Jonathan; D'Acunzo, Pasquale; Pawlik, Monika; Heguy, Adriana; Penikalapati, Sai C; Labuza, Amanda; Pidikiti, Harshitha; Alldred, Melissa J; Ginsberg, Stephen D; Levy, Efrat; Mathews, Paul M
The polymorphic APOE gene is the greatest genetic determinant of sporadic Alzheimer's disease risk: the APOE4 allele increases risk, while the APOE2 allele is neuroprotective compared with the risk-neutral APOE3 allele. The neuronal endosomal system is inherently vulnerable during aging, and APOE4 exacerbates this vulnerability by driving an enlargement of early endosomes and reducing exosome release in the brain of humans and mice. We hypothesized that the protective effects of APOE2 are, in part, mediated through the endosomal pathway. Messenger RNA analyses showed that APOE2 leads to an enrichment of endosomal pathways in the brain when compared with both APOE3 and APOE4. Moreover, we show age-dependent alterations in the recruitment of key endosomal regulatory proteins to vesicle compartments when comparing APOE2 to APOE3. In contrast to the early endosome enlargement previously shown in Alzheimer's disease and APOE4 models, we detected similar morphology and abundance of early endosomes and retromer-associated vesicles within cortical neurons of aged APOE2 targeted-replacement mice compared with APOE3. Additionally, we observed increased brain extracellular levels of endosome-derived exosomes in APOE2 compared with APOE3 mice during aging, consistent with enhanced endosomal cargo clearance by exosomes to the extracellular space. Our findings thus demonstrate that APOE2 enhances an endosomal clearance pathway, which has been shown to be impaired by APOE4 and which may be protective due to APOE2 expression during brain aging.
PMCID:11141728
PMID: 38777335
ISSN: 1600-0854
CID: 5654732
Brain apolipoprotein E levels in mice challenged by a Western diet increase in an allele-dependent manner
Liemisa, Braison; Newbury, Samantha F; Novy, Mariah J; Pasato, Jonathan A; Morales-Corraliza, Jose; Peng, Katherine Y; Mathews, Paul M
Human apolipoprotein E (APOE) is the greatest determinant of genetic risk for memory deficits and Alzheimer's disease (AD). While APOE4 drives memory loss and high AD risk, APOE2 leads to healthy brain aging and reduced AD risk compared to the common APOE3 variant. We examined brain APOE protein levels in humanized mice homozygous for these alleles and found baseline levels to be age- and isoform-dependent: APOE2 levels were greater than APOE3, which were greater than APOE4. Despite the understanding that APOE lipoparticles do not traverse the blood-brain barrier, we show that brain APOE levels are responsive to dietary fat intake. Challenging mice for 6 months on a Western diet high in fat and cholesterol increased APOE protein levels in an allele-dependent fashion with a much greater increase within blood plasma than within the brain. In the brain, APOE2 levels responded most to the Western diet challenge, increasing by 20 % to 30 %. While increased lipoparticles are generally deleterious in the periphery, we propose that higher brain APOE2 levels may represent a readily available pool of beneficial lipid particles for neurons.
PMCID:10696459
PMID: 38058491
ISSN: 2589-9589
CID: 5591282
Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis
Kleffman, Kevin; Levinson, Grace; Rose, Indigo V L; Blumenberg, Lili M; Shadaloey, Sorin A A; Dhabaria, Avantika; Wong, Eitan; Galan-Echevarria, Francisco; Karz, Alcida; Argibay, Diana; Von Itter, Richard; Floristan, Alfredo; Baptiste, Gillian; Eskow, Nicole M; Tranos, James A; Chen, Jenny; Vega Y Saenz de Miera, Eleazar C; Call, Melissa; Rogers, Robert; Jour, George; Wadghiri, Youssef Zaim; Osman, Iman; Li, Yue-Ming; Mathews, Paul; DeMattos, Ronald; Ueberheide, Beatrix; Ruggles, Kelly V; Liddelow, Shane A; Schneider, Robert J; Hernando, Eva
Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. Our unbiased proteomics analysis of melanoma short-term cultures revealed that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. We showed that melanoma cells require amyloid beta (AB) for growth and survival in the brain parenchyma. Melanoma-secreted AB activates surrounding astrocytes to a pro-metastatic, anti-inflammatory phenotype and prevents phagocytosis of melanoma by microglia. Finally, we demonstrate that pharmacological inhibition of AB decreases brain metastatic burden.
PMID: 35262173
ISSN: 2159-8290
CID: 5183542
Expression and proteolytic processing of the amyloid precursor protein is unaffected by the expression of the three human apolipoprotein E alleles in the brains of mice
Novy, Mariah J; Newbury, Samantha F; Liemisa, Braison; Morales-Corraliza, Jose; Alldred, Melissa J; Ginsberg, Stephen D; Mathews, Paul M
The 3 human apolipoprotein E (APOE) gene alleles modify an individual's risk of developing Alzheimer's disease (AD): compared to the risk-neutral APOE ε3 allele, the ε4 allele (APOE4) is strongly associated with increased AD risk while the ε2 allele is protective. Multiple mechanisms have been shown to link APOE4 expression and AD risk, including the possibility that APOE4 increases the expression of the amyloid precursor protein (APP) (Y-W.A. Huang, B. Zhou, A.M. Nabet, M. Wernig, T.C. Südhof, 2019). In this study, we investigated the impact of APOE genotype on the expression, and proteolytic processing of endogenously expressed APP in the brains of mice humanized for the 3 APOE alleles. In contrast to prior studies using neuronal cultures, we found in the brain that both App gene expression, and the levels of APP holoprotein were not affected by APOE genotype. Additionally, our analysis of APP fragments showed that APOE genotype does not impact APP processing in the brain: the levels of both α- and β-cleaved soluble APP fragments (sAPPs) were similar across genotypes, as were the levels of the membrane-associated α- and β-cleaved C-terminal fragments (CTFs) of APP. Lastly, APOE genotype did not impact the level of soluble amyloid beta (Aβ). These findings argue that the APOE-allele-dependent AD risk is independent of the brain expression and processing of APP.
PMID: 34875506
ISSN: 1558-1497
CID: 5099572
Regulation of BACE1 expression after injury is linked to the p75 neurotrophin receptor
Saadipour, Khalil; Tiberi, Alexia; Lomardo, Sylvia; Grajales, Elena; Montroull, Laura; Mañucat-Tan, Noralyn B; LaFrancois, John; Cammer, Michael; Mathews, Paul M; Scharfman, Helen E; Liao, Francesca-Fang; Friedman, Wilma J; Zhou, Xin-Fu; Tesco, Giueseppina; Chao, Moses V
BACE1 is a transmembrane aspartic protease that cleaves various substrates and it is required for normal brain function. BACE1 expression is high during early development, but it is reduced in adulthood. Under conditions of stress and injury, BACE1 levels are increased; however, the underlying mechanisms that drive BACE1 elevation are not well understood. One mechanism associated with brain injury is the activation of injurious p75 neurotrophin receptor (p75), which can trigger pathological signals. Here we report that within 72 h after controlled cortical impact (CCI) or laser injury, BACE1 and p75 are increased and tightly co-expressed in cortical neurons of mouse brain. Additionally, BACE1 is not up-regulated in p75 null mice in response to focal cortical injury, while p75 over-expression results in BACE1 augmentation in HEK-293 and SY5Y cell lines. A luciferase assay conducted in SY5Y cell line revealed that BACE1 expression is regulated at the transcriptional level in response to p75 transfection. Interestingly, this effect does not appear to be dependent upon p75 ligands including mature and pro-neurotrophins. In addition, BACE1 activity on amyloid precursor protein (APP) is enhanced in SY5Y-APP cells transfected with a p75 construct. Lastly, we found that the activation of c-jun n-terminal kinase (JNK) by p75 contributes to BACE1 up-regulation. This study explores how two injury-induced molecules are intimately connected and suggests a potential link between p75 signaling and the expression of BACE1 after brain injury.
PMID: 31422108
ISSN: 1095-9327
CID: 4046542
High resolution approaches for the identification of amyloid fragments in brain
Ross, J A; Mathews, P M; Van Bockstaele, E J
BACKGROUND:.
 CONCLUSIONS: Using novel and highly specific antibodies in combination with electron microscopy may reveal important information about the timing of aberrant protein accumulation, as well as the progression of abnormalities in the endolysosomal systems that sort and clear these peptides.
PMID: 30367888
ISSN: 1872-678x
CID: 3386222
Apolipoprotein E4 genotype compromises brain exosome production
Peng, Katherine Y; Pérez-González, Rocío; Alldred, Melissa J; Goulbourne, Chris N; Morales-Corraliza, Jose; Saito, Mariko; Saito, Mitsuo; Ginsberg, Stephen D; Mathews, Paul M; Levy, Efrat
In addition to being the greatest genetic risk factor for Alzheimer's disease, expression of the ɛ4 allele of apolipoprotein E can lead to cognitive decline during ageing that is independent of Alzheimer's amyloid-β and tau pathology. In human post-mortem tissue and mouse models humanized for apolipoprotein E, we examined the impact of apolipoprotein E4 expression on brain exosomes, vesicles that are produced within and secreted from late-endocytic multivesicular bodies. Compared to humans or mice homozygous for the risk-neutral ɛ3 allele we show that the ɛ4 allele, whether homozygous or heterozygous with an ɛ3 allele, drives lower exosome levels in the brain extracellular space. In mice, we show that the apolipoprotein E4-driven change in brain exosome levels is age-dependent: while not present at age 6 months, it is detectable at 12 months of age. Expression levels of the exosome pathway regulators tumor susceptibility gene 101 (TSG101) and Ras-related protein Rab35 (RAB35) were found to be reduced in the brain at the protein and mRNA levels, arguing that apolipoprotein E4 genotype leads to a downregulation of exosome biosynthesis and release. Compromised exosome production is likely to have adverse effects, including diminishing a cell's ability to eliminate materials from the endosomal-lysosomal system. This reduction in brain exosome levels in 12-month-old apolipoprotein E4 mice occurs earlier than our previously reported brain endosomal pathway changes, arguing that an apolipoprotein E4-driven failure in exosome production plays a primary role in endosomal and lysosomal deficits that occur in apolipoprotein E4 mouse and human brains. Disruption of these interdependent endosomal-exosomal-lysosomal systems in apolipoprotein E4-expressing individuals may contribute to amyloidogenic amyloid-β precursor protein processing, compromise trophic signalling and synaptic function, and interfere with a neuron's ability to degrade material, all of which are events that lead to neuronal vulnerability and higher risk of Alzheimer's disease development. Together, these data suggest that exosome pathway dysfunction is a previously unappreciated component of the brain pathologies that occur as a result of apolipoprotein E4 expression.
PMID: 30496349
ISSN: 1460-2156
CID: 3500172