Medical Hypotheses xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Does metabolic failure at the synapse cause Alzheimer’s disease? q Peter A. Engel ⇑ Geriatric Research, Education and Clinical Center, VA Boston Healthcare System, Harvard Medical School, United States
a r t i c l e
i n f o
Article history: Received 18 September 2014 Accepted 15 October 2014 Available online xxxx
a b s t r a c t Alzheimer’s disease (AD) a neurodegenerative disorder of widely distributed cortical networks evolves over years while A beta (Ab) oligomer neurotoxicity occurs within seconds to minutes. This disparity combined with disappointing outcomes of anti-amyloid clinical trials challenges the centrality of Ab as principal mediator of neurodegeneration. Reconsideration of late life AD as the end-product of intermittent regional failure of the neuronal support system to meet the needs of vulnerable brain areas offers an alternative point of view. This model introduces four ideas: (1) That Ab is a synaptic signaling peptide that becomes toxic in circumstances of metabolic stress. (2) That intense synaptic energy and maintenance requirements of cortical hubs may exceed resources during peak demand initiating a neurotoxic cascade in these selectively vulnerable regions. (3) That axonal transport to and from neuron soma cannot account fully for high mitochondrial densities and other requirements of distant terminal axons. (4) That neurons as specialists in information management, delegate generic support functions to astrocytes and other cell types. Astrocytes use intercellular transport by exosomes and tunneling nanotubes (TNTs) to deliver mitochondria, substrates and protein reprocessing services to axonal sites distant from neuronal soma. This viewpoint implicates the brain’s support system and its disruption by various age and diseaserelated insults as significant mediators of neurodegenerative disease. A better understanding of this system should broaden concepts of neurodegeneration and facilitate development of effective treatments. Ó 2014 Published by Elsevier Ltd.
Introduction and background Alzheimer’s disease (AD) the most common dementia of late life develops over decades and is characterized pathologically by the accumulation of extracellular b amyloid (Ab) plaques and intraneuronal tangles of hyperphosphorylated tau protein. Despite voluminous human and animal model research on AD, a vast proliferation of new information on the biomolecular processes associated with AD and unequivocal evidence of Ab oligomer toxicity, the fundamental processes driving this chronic progressive disease remain elusive as does the emergence of effective treatments. Moreover Ab has an established reputation as a toxin while its potential physiological functions have been relatively ignored [1].
q
Study funding: unfunded.
⇑ Address: VA Boston Healthcare System, 150 S. Huntington Ave., Boston, MA 02130, United States. Tel.: +1 857 364 3656; fax: +1 857 364 4544. E-mail address: [email protected]
AD is a disease of the brain, and brain as a highly specialized information processing organ possesses several unique characteristics. Among these are complex neuronal connectivity in widely distributed cortical networks, synaptic plasticity, myelinated axons bearing synapses at vast distances from cell soma and energydependent axonal transport in which tau is a critical component [2–8]. To optimize information management efficiency, neurons rely on a complex support system comprised of astrocytes, oligodendrocytes, pericytes and capillaries. Astrocytes, outnumbering neurons 1.4/1 serve as intermediaries between neurons and capillaries as key components of the blood–brain barrier (BBB), a unique anatomical characteristic of the central nervous system (CNS) [9–11]. These features, among others accompanied by intense energy demands define the brain’s exceptional storage and information processing capacity as well as its vulnerabilities [12–16]. The distinguishing characteristics of brain create a context in which to understand degenerative brain disorders such as AD as the product of dysregulations in energy, substrate supply and waste management that result in damage to the most vulnerable
http://dx.doi.org/10.1016/j.mehy.2014.10.013 0306-9877/Ó 2014 Published by Elsevier Ltd.
Please cite this article in press as: Engel PA. Does metabolic failure at the synapse cause Alzheimer’s disease? Med Hypotheses (2014), http://dx.doi.org/ 10.1016/j.mehy.2014.10.013
2
P.A. Engel / Medical Hypotheses xxx (2014) xxx–xxx
components of the brain. Transient deficiencies in these systems are significant since metabolically-induced injury may occur within seconds to minutes, a time frame that parallels many CNS physiological processes. During peak demand insufficient energy and substrate promote a cascade of negative events including an increase in free radicals, apoptosis in post-mitotic neurons, tau protein hyperphosphorylation and increased Ab concentrations within minutes and plaque aggregation within hours [17–21]. In the dynamic energy intensive perisynaptic environment, new synapse formation and synapse regression can occur within minutes. Both processes may require protein synthesis, immediate substrate availability, effective waste disposal and high mitochondrial densities [4,22–24]. Timely availability is essential for successful synaptic dynamics and neurotransmission while in the longest axons (10–12 cm in brain, up to 100 cm for pyramidal motor neurons), axonal transport speed limits and biological product half lives may not be compatible with the concept of neuron soma as principal supplier to terminal axons [25,26]. This discussion will reconsider the pathogenesis of late life Alzheimer’s disease from the viewpoint of the neuronal support system with specific focus on metabolic failure at the synapse. Intermittent metabolic failure refers to a transient deficit of ATP, glucose, oxygen and other substrates or failures of maintenance processes at microscopic and regional levels. The cortical nature of AD directs attention to transmodal neocortex and cortical hubs of widely distributed neuronal networks, regions of high energy demand and constant synaptic remodeling [2,3,27–29]. The relevance of intermittent metabolic failure to the pathogenesis of AD may be examined from many vantage points. Among these are the effects of metabolic failure on Ab metabolism [17], tau phosphorylation [8], misfolding of these proteins and their transynaptic propagation [30–32], genetic factors, inflammation and response to injury [33]. Aging, a pro-inflammatory state modulates all of these variables and is strongly associated with AD risk [34–43]. To provide focus in this maze of variables, Ab will serve as a principal reference point in which to format the major ideas in the paper. The most important of these are the impacts of power failure and lapses of quality control on disease expression. This perspective serves to reframe AD as a disorder of the neuronal support system, rather than the neuron. So viewed consideration of AD invites exploration of the following concepts: (1) That Ab is a signaling peptide with important physiological functions. Ab toxicity occurs in the context of defective regulation or metabolism. (2) That intermittent power failure is a significant driver of neurotoxicity and major determinant of late onset AD, mediated in part by supraphysiological levels of oligomeric Ab and hyperphosphorylated tau [44–47]. (3) That axonal transport alone cannot meet the dynamic supply and maintenance needs of terminal axons at great distances from neuron soma. (4) That neurons enhance information processing efficiency by ‘‘outsourcing’’ generic functions, including the efficient provision of mitochondria at critical locations. Astrocytes are principal candidates for this function and have devised mechanisms of intercellular organelle exchange. Ab is a signaling peptide Ab toxicity, particularly in its oligomeric forms is well established but it is increasingly clear that Ab, its precursor, amyloid precursor protein (APP) and APP derived peptides have a variety of physiologic functions [48–51]. Ab is released at the synapse as a function of synaptic activity such that increased activity generates increased interstitial concentrations [52]. Picomolar
concentrations of Ab 1–42 enhance long term potentiation (LTP) a physiological substrate of new memory formation, while higher nanomolar concentrations promote long term depression (LTD) that may also be physiologic [53–57]. In AD mouse models, following vibressectomy and loss of sensory input, synaptic activity and Ab release diminish in barrel cortex and fewer amyloid plaques appear. Concurrently, dendritic shrinkage and rarefaction occur with corresponding decrements in memory [52,58,59]. Many putative physiological functions of Ab occur within minutes to hours, times that are comparable to those of synaptogenesis, synaptolysis, protein synthesis, dendritic spine changes, LTP and LTD induction [4,22–24,52,54,60]. Hence, Ab synaptic release is comparable to known pre-synaptic signaling peptides including neuropeptide Y, somatostatin and brain derived neurotrophic factor. The identification of post-synaptic receptors for these peptides and the proposed existence of several Ab receptor counterparts reinforces this idea [61,62]. Tight regulation of signaling peptides is essential for their physiologic actions. In the case of Ab, the integrity of Ab signaling and effective clearance mechanisms are intimately related to the brain’s energy and waste management resources.
Intermittent metabolic failure drives neurotoxicity Human brain is energy-avid comprising 2% of body mass while consuming 20–25% of resting state energy. Most energy is expended at synapses and nodes of Ranvier to reverse ion fluxes of synaptic and action potentials. Another 25% drives housekeeping activities such as molecule synthesis, organelle trafficking and waste management [12,13]. Sites of neurotransmission and synaptic plasticity in cortical hubs and networks are of specific interest in AD as regions where increased Ab release and aggregation are most likely to occur [3]. Most cortical hub regions are located in late maturing thinly myelinated areas including the multimodal association areas where smaller numbers of oligodendrocytes are available for myelin maintenance [2]. Even under physiological circumstances peak energy needs in these regions may transiently exceed resources. Gamma oscillations (GO) (30–80 Hz), proposed synchronizers of neuronal networks associated with memory formation and sensory processing are observed in hippocampus, parietal and prefrontal regions [15,63]. Localized energy, oxygen and substrate requirements of GO can reach the limits of mitochondrial oxidation capacity [63]. Similarly, peak energy demands of LTP have been associated with maximum ATP availability [64]. Focal energy needs of GO and LTP are comparable to those of seizures and in the setting of compromised resources may have comparably adverse effects including generation of Ab neuritic plaques and neuronal cell death by apoptosis or necrosis [63,65,66]. In Alzheimer’s disease structural and functional imaging as well as postmortem studies indicate reduced metabolic activity, cortical thinning and Ab deposition in areas that overlap substantially with regions of high synaptic and metabolic activity in normal brain. These include key regions of the default mode network (Fig. 1) [3,15,29,67–69]. These data suggest that cortical areas characterized by high energy needs and long projections of thinly myelinated fibers constitute selectively vulnerable sites in which intermittent energy or metabolic failure is more likely to occur. In familial Alzheimer’s disease chronic excess Ab substrate can overwhelm local waste management capacities, but in most cases failures of Ab disposal rather than overproduction is the principal pathological driver of Ab plaque accumulations [52]. Maintenance of quality control, in turn, is mediated by vascular supply, BBB function, brain immunoreactivity, apoprotein cholesterol transport, and efficient free radical scavenging within a context of numerous genetic and environmental variables.
Please cite this article in press as: Engel PA. Does metabolic failure at the synapse cause Alzheimer’s disease? Med Hypotheses (2014), http://dx.doi.org/ 10.1016/j.mehy.2014.10.013
3
P.A. Engel / Medical Hypotheses xxx (2014) xxx–xxx
Fig. 1. Areas of late, thin myelination overlap with cortical hubs and dense areas of Ab deposition in AD. Cortical hubs (circles) are principally located in the shaded regions representing areas of late myelination (A) [120], low myelin density (B) [2,28], peak metabolic activity (C) [3], and high Ab density in AD (D) [3]. (E), Is a composite of A–D. Cortical hub identification: 1, dorsolateral prefrontal, 2, lateral temporal, 3, inferior parietal, 4, medial prefrontal, 5, posterior cingulate. Default network hubs 1, 3, and 5 are active across task states [3]. Left medial cortex inverted for ease of comparison. Original drawings reflect data from cited sources.
Amyloid b: mismanagement of this signaling peptide promotes AD pathology Ab production, aggregation and clearance may be profoundly affected by both physiologic and adverse brain conditions, variables that influence disease expression. Hypoxia, hypoglycemia, ischemia, injury and inflammation increase oxidative stress and are associated with increased production and interstitial levels of Ab [17–21]. Episodic metabolic failure in areas of high synaptic activity promotes Ab release, impaired processing and rapid aggregation that occur in locally hypoxic or hypoglycemic environments. In vitro, oxygen and glucose deprivation of rat brain capillary endothelial cells provokes a 250% increase in Ab through up-regulation of b secretase, enhanced c-secretase cleavage of the AbAPP peptide and down-regulation of neprilysin, an Ab catabolizer [17,19,20]. In vivo, cortical plaques develop focally within 24 h in AD mouse models [70]. Moreover, Ab plaque formation is not specific to AD but occurs in other compromised circumstances characterized by increased Ab release or impaired clearance. Microstrokes induce new amyloid plaques in mouse models of AD [21,71]. Ab plaques develop within hours following traumatic brain injury, and are evident at an initial observation time of 7 days in animal studies of stroke [72–74]. Traumatic brain hemorrhage up-regulates generation of hyperphosphorylated tau, APP, Ab and oligomeric Ab over 1–7 days [75]. Increased oxidative stress characterizes all these circumstances and oxidative stress is a mediator of apoptosis, a product of stress-induced cell cycle re-entry in post mitotic neurons [76]. High concentrations of Ab may induce cell cycle re-entry as well, a notable observation since Ab levels are increased at interstitial sites of high synaptic activity [52,77].
are assumed to occur in the cell body, a potentially problematic system for the longest axons [78]. In addition to damaged mitochondria, worn out ubiquitinated proteins are reportedly transported retrograde to neuron soma for proteasome reprocessing placing enormous demands on bidirectional axonal transport [5,25,78]. These functions are not obviously compatible with reported axonal transport speeds for mitochondria, 99% of the cell structure and content that is purportedly serviced by the remote neuron soma [6,26]. The supply and repair needs of distal axons are considerable entailing new protein synthesis, cell membrane formation, ligand reprocessing and numerous other functions. High metabolic demands at the synapse and nodes of Ranvier require dense populations of mitochondria, effective removal of damaged mitochondria by mitophagy and efficient delivery of fresh mitochondria to these energy intensive sites. Both mitochondrial biogenesis and disposal
Table 1 Axonal transport speeds; adapted from Millecamps [5].
Golgi-derived vesicles (containing neurotransmitters) Neurosecretory granules (containing hormones, neurotropins) Endosomal recycling vesicles (containing hormones, neurotropins) Viruses mRNA Mitochondria and lysosomes Autophagosomes Membrane proteins and enzymes
Millimeters/day
Direction
200–400
Anterograde
50–400
Retrograde
200
Retrograde
200 20–200
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Does metabolic failure at the synapse cause Alzheimer’s disease? q Peter A. Engel ⇑ Geriatric Research, Education and Clinical Center, VA Boston Healthcare System, Harvard Medical School, United States
a r t i c l e
i n f o
Article history: Received 18 September 2014 Accepted 15 October 2014 Available online xxxx
a b s t r a c t Alzheimer’s disease (AD) a neurodegenerative disorder of widely distributed cortical networks evolves over years while A beta (Ab) oligomer neurotoxicity occurs within seconds to minutes. This disparity combined with disappointing outcomes of anti-amyloid clinical trials challenges the centrality of Ab as principal mediator of neurodegeneration. Reconsideration of late life AD as the end-product of intermittent regional failure of the neuronal support system to meet the needs of vulnerable brain areas offers an alternative point of view. This model introduces four ideas: (1) That Ab is a synaptic signaling peptide that becomes toxic in circumstances of metabolic stress. (2) That intense synaptic energy and maintenance requirements of cortical hubs may exceed resources during peak demand initiating a neurotoxic cascade in these selectively vulnerable regions. (3) That axonal transport to and from neuron soma cannot account fully for high mitochondrial densities and other requirements of distant terminal axons. (4) That neurons as specialists in information management, delegate generic support functions to astrocytes and other cell types. Astrocytes use intercellular transport by exosomes and tunneling nanotubes (TNTs) to deliver mitochondria, substrates and protein reprocessing services to axonal sites distant from neuronal soma. This viewpoint implicates the brain’s support system and its disruption by various age and diseaserelated insults as significant mediators of neurodegenerative disease. A better understanding of this system should broaden concepts of neurodegeneration and facilitate development of effective treatments. Ó 2014 Published by Elsevier Ltd.
Introduction and background Alzheimer’s disease (AD) the most common dementia of late life develops over decades and is characterized pathologically by the accumulation of extracellular b amyloid (Ab) plaques and intraneuronal tangles of hyperphosphorylated tau protein. Despite voluminous human and animal model research on AD, a vast proliferation of new information on the biomolecular processes associated with AD and unequivocal evidence of Ab oligomer toxicity, the fundamental processes driving this chronic progressive disease remain elusive as does the emergence of effective treatments. Moreover Ab has an established reputation as a toxin while its potential physiological functions have been relatively ignored [1].
q
Study funding: unfunded.
⇑ Address: VA Boston Healthcare System, 150 S. Huntington Ave., Boston, MA 02130, United States. Tel.: +1 857 364 3656; fax: +1 857 364 4544. E-mail address: [email protected]
AD is a disease of the brain, and brain as a highly specialized information processing organ possesses several unique characteristics. Among these are complex neuronal connectivity in widely distributed cortical networks, synaptic plasticity, myelinated axons bearing synapses at vast distances from cell soma and energydependent axonal transport in which tau is a critical component [2–8]. To optimize information management efficiency, neurons rely on a complex support system comprised of astrocytes, oligodendrocytes, pericytes and capillaries. Astrocytes, outnumbering neurons 1.4/1 serve as intermediaries between neurons and capillaries as key components of the blood–brain barrier (BBB), a unique anatomical characteristic of the central nervous system (CNS) [9–11]. These features, among others accompanied by intense energy demands define the brain’s exceptional storage and information processing capacity as well as its vulnerabilities [12–16]. The distinguishing characteristics of brain create a context in which to understand degenerative brain disorders such as AD as the product of dysregulations in energy, substrate supply and waste management that result in damage to the most vulnerable
http://dx.doi.org/10.1016/j.mehy.2014.10.013 0306-9877/Ó 2014 Published by Elsevier Ltd.
Please cite this article in press as: Engel PA. Does metabolic failure at the synapse cause Alzheimer’s disease? Med Hypotheses (2014), http://dx.doi.org/ 10.1016/j.mehy.2014.10.013
2
P.A. Engel / Medical Hypotheses xxx (2014) xxx–xxx
components of the brain. Transient deficiencies in these systems are significant since metabolically-induced injury may occur within seconds to minutes, a time frame that parallels many CNS physiological processes. During peak demand insufficient energy and substrate promote a cascade of negative events including an increase in free radicals, apoptosis in post-mitotic neurons, tau protein hyperphosphorylation and increased Ab concentrations within minutes and plaque aggregation within hours [17–21]. In the dynamic energy intensive perisynaptic environment, new synapse formation and synapse regression can occur within minutes. Both processes may require protein synthesis, immediate substrate availability, effective waste disposal and high mitochondrial densities [4,22–24]. Timely availability is essential for successful synaptic dynamics and neurotransmission while in the longest axons (10–12 cm in brain, up to 100 cm for pyramidal motor neurons), axonal transport speed limits and biological product half lives may not be compatible with the concept of neuron soma as principal supplier to terminal axons [25,26]. This discussion will reconsider the pathogenesis of late life Alzheimer’s disease from the viewpoint of the neuronal support system with specific focus on metabolic failure at the synapse. Intermittent metabolic failure refers to a transient deficit of ATP, glucose, oxygen and other substrates or failures of maintenance processes at microscopic and regional levels. The cortical nature of AD directs attention to transmodal neocortex and cortical hubs of widely distributed neuronal networks, regions of high energy demand and constant synaptic remodeling [2,3,27–29]. The relevance of intermittent metabolic failure to the pathogenesis of AD may be examined from many vantage points. Among these are the effects of metabolic failure on Ab metabolism [17], tau phosphorylation [8], misfolding of these proteins and their transynaptic propagation [30–32], genetic factors, inflammation and response to injury [33]. Aging, a pro-inflammatory state modulates all of these variables and is strongly associated with AD risk [34–43]. To provide focus in this maze of variables, Ab will serve as a principal reference point in which to format the major ideas in the paper. The most important of these are the impacts of power failure and lapses of quality control on disease expression. This perspective serves to reframe AD as a disorder of the neuronal support system, rather than the neuron. So viewed consideration of AD invites exploration of the following concepts: (1) That Ab is a signaling peptide with important physiological functions. Ab toxicity occurs in the context of defective regulation or metabolism. (2) That intermittent power failure is a significant driver of neurotoxicity and major determinant of late onset AD, mediated in part by supraphysiological levels of oligomeric Ab and hyperphosphorylated tau [44–47]. (3) That axonal transport alone cannot meet the dynamic supply and maintenance needs of terminal axons at great distances from neuron soma. (4) That neurons enhance information processing efficiency by ‘‘outsourcing’’ generic functions, including the efficient provision of mitochondria at critical locations. Astrocytes are principal candidates for this function and have devised mechanisms of intercellular organelle exchange. Ab is a signaling peptide Ab toxicity, particularly in its oligomeric forms is well established but it is increasingly clear that Ab, its precursor, amyloid precursor protein (APP) and APP derived peptides have a variety of physiologic functions [48–51]. Ab is released at the synapse as a function of synaptic activity such that increased activity generates increased interstitial concentrations [52]. Picomolar
concentrations of Ab 1–42 enhance long term potentiation (LTP) a physiological substrate of new memory formation, while higher nanomolar concentrations promote long term depression (LTD) that may also be physiologic [53–57]. In AD mouse models, following vibressectomy and loss of sensory input, synaptic activity and Ab release diminish in barrel cortex and fewer amyloid plaques appear. Concurrently, dendritic shrinkage and rarefaction occur with corresponding decrements in memory [52,58,59]. Many putative physiological functions of Ab occur within minutes to hours, times that are comparable to those of synaptogenesis, synaptolysis, protein synthesis, dendritic spine changes, LTP and LTD induction [4,22–24,52,54,60]. Hence, Ab synaptic release is comparable to known pre-synaptic signaling peptides including neuropeptide Y, somatostatin and brain derived neurotrophic factor. The identification of post-synaptic receptors for these peptides and the proposed existence of several Ab receptor counterparts reinforces this idea [61,62]. Tight regulation of signaling peptides is essential for their physiologic actions. In the case of Ab, the integrity of Ab signaling and effective clearance mechanisms are intimately related to the brain’s energy and waste management resources.
Intermittent metabolic failure drives neurotoxicity Human brain is energy-avid comprising 2% of body mass while consuming 20–25% of resting state energy. Most energy is expended at synapses and nodes of Ranvier to reverse ion fluxes of synaptic and action potentials. Another 25% drives housekeeping activities such as molecule synthesis, organelle trafficking and waste management [12,13]. Sites of neurotransmission and synaptic plasticity in cortical hubs and networks are of specific interest in AD as regions where increased Ab release and aggregation are most likely to occur [3]. Most cortical hub regions are located in late maturing thinly myelinated areas including the multimodal association areas where smaller numbers of oligodendrocytes are available for myelin maintenance [2]. Even under physiological circumstances peak energy needs in these regions may transiently exceed resources. Gamma oscillations (GO) (30–80 Hz), proposed synchronizers of neuronal networks associated with memory formation and sensory processing are observed in hippocampus, parietal and prefrontal regions [15,63]. Localized energy, oxygen and substrate requirements of GO can reach the limits of mitochondrial oxidation capacity [63]. Similarly, peak energy demands of LTP have been associated with maximum ATP availability [64]. Focal energy needs of GO and LTP are comparable to those of seizures and in the setting of compromised resources may have comparably adverse effects including generation of Ab neuritic plaques and neuronal cell death by apoptosis or necrosis [63,65,66]. In Alzheimer’s disease structural and functional imaging as well as postmortem studies indicate reduced metabolic activity, cortical thinning and Ab deposition in areas that overlap substantially with regions of high synaptic and metabolic activity in normal brain. These include key regions of the default mode network (Fig. 1) [3,15,29,67–69]. These data suggest that cortical areas characterized by high energy needs and long projections of thinly myelinated fibers constitute selectively vulnerable sites in which intermittent energy or metabolic failure is more likely to occur. In familial Alzheimer’s disease chronic excess Ab substrate can overwhelm local waste management capacities, but in most cases failures of Ab disposal rather than overproduction is the principal pathological driver of Ab plaque accumulations [52]. Maintenance of quality control, in turn, is mediated by vascular supply, BBB function, brain immunoreactivity, apoprotein cholesterol transport, and efficient free radical scavenging within a context of numerous genetic and environmental variables.
Please cite this article in press as: Engel PA. Does metabolic failure at the synapse cause Alzheimer’s disease? Med Hypotheses (2014), http://dx.doi.org/ 10.1016/j.mehy.2014.10.013
3
P.A. Engel / Medical Hypotheses xxx (2014) xxx–xxx
Fig. 1. Areas of late, thin myelination overlap with cortical hubs and dense areas of Ab deposition in AD. Cortical hubs (circles) are principally located in the shaded regions representing areas of late myelination (A) [120], low myelin density (B) [2,28], peak metabolic activity (C) [3], and high Ab density in AD (D) [3]. (E), Is a composite of A–D. Cortical hub identification: 1, dorsolateral prefrontal, 2, lateral temporal, 3, inferior parietal, 4, medial prefrontal, 5, posterior cingulate. Default network hubs 1, 3, and 5 are active across task states [3]. Left medial cortex inverted for ease of comparison. Original drawings reflect data from cited sources.
Amyloid b: mismanagement of this signaling peptide promotes AD pathology Ab production, aggregation and clearance may be profoundly affected by both physiologic and adverse brain conditions, variables that influence disease expression. Hypoxia, hypoglycemia, ischemia, injury and inflammation increase oxidative stress and are associated with increased production and interstitial levels of Ab [17–21]. Episodic metabolic failure in areas of high synaptic activity promotes Ab release, impaired processing and rapid aggregation that occur in locally hypoxic or hypoglycemic environments. In vitro, oxygen and glucose deprivation of rat brain capillary endothelial cells provokes a 250% increase in Ab through up-regulation of b secretase, enhanced c-secretase cleavage of the AbAPP peptide and down-regulation of neprilysin, an Ab catabolizer [17,19,20]. In vivo, cortical plaques develop focally within 24 h in AD mouse models [70]. Moreover, Ab plaque formation is not specific to AD but occurs in other compromised circumstances characterized by increased Ab release or impaired clearance. Microstrokes induce new amyloid plaques in mouse models of AD [21,71]. Ab plaques develop within hours following traumatic brain injury, and are evident at an initial observation time of 7 days in animal studies of stroke [72–74]. Traumatic brain hemorrhage up-regulates generation of hyperphosphorylated tau, APP, Ab and oligomeric Ab over 1–7 days [75]. Increased oxidative stress characterizes all these circumstances and oxidative stress is a mediator of apoptosis, a product of stress-induced cell cycle re-entry in post mitotic neurons [76]. High concentrations of Ab may induce cell cycle re-entry as well, a notable observation since Ab levels are increased at interstitial sites of high synaptic activity [52,77].
are assumed to occur in the cell body, a potentially problematic system for the longest axons [78]. In addition to damaged mitochondria, worn out ubiquitinated proteins are reportedly transported retrograde to neuron soma for proteasome reprocessing placing enormous demands on bidirectional axonal transport [5,25,78]. These functions are not obviously compatible with reported axonal transport speeds for mitochondria, 99% of the cell structure and content that is purportedly serviced by the remote neuron soma [6,26]. The supply and repair needs of distal axons are considerable entailing new protein synthesis, cell membrane formation, ligand reprocessing and numerous other functions. High metabolic demands at the synapse and nodes of Ranvier require dense populations of mitochondria, effective removal of damaged mitochondria by mitophagy and efficient delivery of fresh mitochondria to these energy intensive sites. Both mitochondrial biogenesis and disposal
Table 1 Axonal transport speeds; adapted from Millecamps [5].
Golgi-derived vesicles (containing neurotransmitters) Neurosecretory granules (containing hormones, neurotropins) Endosomal recycling vesicles (containing hormones, neurotropins) Viruses mRNA Mitochondria and lysosomes Autophagosomes Membrane proteins and enzymes
Millimeters/day
Direction
200–400
Anterograde
50–400
Retrograde
200
Retrograde
200 20–200
