The early events of Alzheimer's disease pathology: from mitochondrial dysfunction to BDNF axonal transport deficits

Ye, Xuan; Tai, Wenjiao; Zhang, Dan

doi:10.1016/j.neurobiolaging.2011.11.004

Cited by 75 publications

(58 citation statements)

References 95 publications

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“…These "signaling endosomes" are then retrogradely transported to the corresponding cell bodies to transmit NGF trophic signals (50,98). Thus, axonal trafficking mediated by Rab5 + endosomes plays a critical role in maintaining the trophic status of BFCNs, and alteration in these aspects could potentially disrupt axonal transport, resulting in neurodegenerative disorders (88,(99)(100)(101)(102)(103)(104)(105)(106)(107).…”

Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein–mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration

Xu¹,

Weissmiller²,

White³

et al. 2016

Journal of Clinical Investigation

150

242

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R e s e a R c h a R t i c l e1 8 1 6jci.org Volume 126Number 5 May 2016 26, 54, 55). We assayed the level of GTP-Rab5 in brains of 12-monthold Ts65Dn and 2N mice following a published protocol (56). As previously reported (28), the level of full-length APP in Ts65Dn was approximately 1.5-fold than in 2N samples ( We next tested whether the increase in App gene dose in Ts65Dn BFCNs was responsible for enlargement of Rab5 + endosomes (Figure 1). By immunoblotting, the APP siRNA caused an approximately 30% reduction in the level of full-length APP, as compared with control siRNA ( Figure 2E). Rab5 + puncta in BFCNs treated with either the APP siRNA or control siRNA were analyzed (Figure 2, F and G) as in Figure 1. Large, sometimes lobulated Rab5 + puncta were seen in cultures treated with the control siRNA, whereas these structures were typically smaller and rounded in cultures treated with the APP siRNA ( Figure 2G). Treatment with the APP siRNA significantly reduced the size of Rab5 + puncta in Ts65Dn neurons to a value equivalent to that in 2N neurons ( Figure 2F). Thus, increased App gene dose is necessary for increased Rab5 activation and for early endosome enlargement in Ts65Dn neurons.Full-length APP and β-CTF caused enlargement of early endosomes in PC12 cells. To determine how increased APP expression caused an increase in Rab5 activation, we asked which APP product(s) were responsible (Supplemental Figure 1A). We transfected PC12M cells with full-length APP-GFP, C99-GFP (β-CTF), C83-GFP (α-CTF), or AICD-GFP and examined endosomes by live cell imaging (Supplemental Figure 1B). Bright foci of GFP + intracellular structures were present in PC12M cells that overexpressed APP-GFP or C99-GFP. In contrast, cells expressing C83-GFP or AICD-GFP showed diffuse, hazy signals for GFP, with occasional foci in C83-GFP cells. In APP-GFP and C99-GFP cells, the GFP + intracellular structures were, on average, approximately 2 μm 2 (Supplemental Figure 1E). GFP signals in C83-GFP or AICD-GFP cells contained speckled small puncta within the haze, as well as a small number of larger bright puncta, as seen in cells expressing C99-GFP and APP-GFP (Supplemental Figure 1B). However, the average puncta size in C83-GFP and AICD-GFP cells was approximately 1.2 and 1.3 μm 2 , respectively. Thus, overexpressing APP and β-CTF, but not α-CTF or AICD, routinely induced formation of enlarged, bright intracellular structures. We also tested two APP mutants: APP M596V and APP SWE . APP M596V , which abolishes β-secretase cleavage, prevents production of β-CTF (57); APP SWE enhances β-secretase cleavage to increase the level of β-CTF (57). Both induced the formation of enlarged intracellular structures (Supplemental Figure 1C).We examined colocalization of APP or C99 with Rab5 in cotransfection experiments; APP-mCherry with GFP-Rab5 WT ( Figure 3B); C99-GFP with mCherry-Rab5 WT ( Figure 3C); and Rab5 + endosomes (26, 28, 37) was correlated with reduced endosomal trafficking and signaling of nerve growth factor (NGF), leading to degeneration...

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Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein–mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration

Xu¹,

Weissmiller²,

White³

et al. 2016

Journal of Clinical Investigation

150

242

View full text Add to dashboard Cite

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“…As pointed out by Reagan [138], Stranahan and Mattson [139] and others [140,141], there are significant pathophysiological similarities between obesity-/DM-, and stress-related mood disorders. Common mechanisms may include mitochondrial dysfunction, insulin resistance, neuroinflammation, oxidative stress, abnormal brain lipid metabolism, or BDNF deficits.…”

Section: Metabolic Syndromementioning

confidence: 99%

Posttraumatic Stress Disorder and Cardiometabolic Disease

Levine¹,

Levine

Levine³

2013

Cardiology

132

118

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The need for addressing posttraumatic stress disorder (PTSD) among combat veterans returning from Afghanistan and Iraq is a growing public health concern. Current PTSD management addresses psychiatric parameters of this condition. However, PTSD is not simply a psychiatric disorder. Traumatic stress increases the risk for inflammation-related somatic diseases and early mortality. The metabolic syndrome reflects the increased health risk associated with combat stress and PTSD. Obesity, dyslipidemia, hypertension, diabetes mellitus, and cardiovascular disease are prevalent among PTSD patients. However, there has been little appreciation for the need to address these somatic PTSD comorbidities. Medical professionals treating this vulnerable population should screen patients for cardiometabolic risk factors and avail themselves of existing preventive diet, exercise, and pharmacologic modalities that will reduce such risk factors and improve overall long-term health outcomes and quality of life. There is the promise that cardiometabolic preventive therapy complementing psychiatric intervention may, in turn, help improve the posttraumatic stress system dysregulation and favorably impact psychiatric and neurologic function.

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“…In contrast, under AD conditions, amyloid-beta prevents the binding of BDNF to NTRK2 receptor, thereby blocking BDNF-NTRK2 downstream signaling. This blockade leads to the repression of neuron survival, differentiation, and growth, so that abnormal APP processing and amyloidbeta production has been experimentally shown to attenuate BDNF-NTRK2 signaling [10]. UCHL1 activity is repressed by amyloid-beta, which in turn impairs BDNF-NTRK2-mediated downstream signaling, leading to diminished synaptic plasticity and neuronal survival [11].…”

Section: App Biology Models Representing Normal Versus Disease Procesmentioning

confidence: 99%

Computable cause‐and‐effect models of healthy and Alzheimer's disease states and their mechanistic differential analysis

Kodamullil

Younesi

Naz

et al. 2015

Alzheimer's & Dementia

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The early events of Alzheimer's disease pathology: from mitochondrial dysfunction to BDNF axonal transport deficits

Cited by 75 publications

References 95 publications

Amyloid precursor protein–mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration

Amyloid precursor protein–mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration

Posttraumatic Stress Disorder and Cardiometabolic Disease

Computable cause‐and‐effect models of healthy and Alzheimer's disease states and their mechanistic differential analysis

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