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J Neurosci
. 2010 Nov 10;30(45):14946–14954. doi: 10.1523/JNEUROSCI.4305-10.2010
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AMYLOID-INDEPENDENT MECHANISMS IN ALZHEIMER'S DISEASE PATHOGENESIS
Sanjay W Pimplikar
SANJAY W PIMPLIKAR
1Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, and
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University,
Cleveland, Ohio 44195,
Find articles by Sanjay W Pimplikar
1,✉, Ralph A Nixon
RALPH A NIXON
2Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, New York,
10962, and Departments of Psychiatry and Cell Biology, New York University
Langone Medical Center, New York, New York 10016,
Find articles by Ralph A Nixon
2, Nikolaos K Robakis
NIKOLAOS K ROBAKIS
3Departments of Psychiatry and Neuroscience, Center for Molecular Biology and
Genetics of Neurodegeneration, Mount Sinai School of Medicine, New York, New
York 10029,
Find articles by Nikolaos K Robakis
3, Jie Shen
JIE SHEN
4Center for Neurologic Diseases, Program in Neuroscience, Brigham and Women's
Hospital, Harvard Medical School, Boston, Massachusetts 02115, and
Find articles by Jie Shen
4, Li-Huei Tsai
LI-HUEI TSAI
5Department of Brain and Cognitive Sciences, Picower Institute for Learning and
Memory, Massachusetts Institute of Technology, and Howard Hughes Medical
Institute, Cambridge, Massachusetts 02139
Find articles by Li-Huei Tsai
5
* Author information
* Article notes
* Copyright and License information
1Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, and
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University,
Cleveland, Ohio 44195,
2Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, New York,
10962, and Departments of Psychiatry and Cell Biology, New York University
Langone Medical Center, New York, New York 10016,
3Departments of Psychiatry and Neuroscience, Center for Molecular Biology and
Genetics of Neurodegeneration, Mount Sinai School of Medicine, New York, New
York 10029,
4Center for Neurologic Diseases, Program in Neuroscience, Brigham and Women's
Hospital, Harvard Medical School, Boston, Massachusetts 02115, and
5Department of Brain and Cognitive Sciences, Picower Institute for Learning and
Memory, Massachusetts Institute of Technology, and Howard Hughes Medical
Institute, Cambridge, Massachusetts 02139
✉
Correspondence should be addressed to Sanjay W. Pimplikar at the above address.
pimplis@ccf.org
✉
Corresponding author.
SERIES INFORMATION
Mini-Symposium
Received 2010 Aug 16; Revised 2010 Sep 15; Accepted 2010 Sep 16.
Copyright © 2010 the authors 0270-6474/10/3014946-09$15.00/0
PMC Copyright notice
PMCID: PMC3426835 NIHMSID: NIHMS251205 PMID: 21068297
ABSTRACT
Despite the progress of the past two decades, the cause of Alzheimer's disease
(AD) and effective treatments against it remain elusive. The hypothesis that
amyloid-β (Aβ) peptides are the primary causative agents of AD retains
significant support among researchers. Nonetheless, a growing body of evidence
shows that Aβ peptides are unlikely to be the sole factor in AD etiology.
Evidence that Aβ/amyloid-independent factors, including the actions of
AD-related genes, also contribute significantly to AD pathogenesis was presented
in a symposium at the 2010 Annual Meeting of the Society for Neuroscience. Here
we summarize the studies showing how amyloid-independent mechanisms cause
defective endo-lysosomal trafficking, altered intracellular signaling cascades,
or impaired neurotransmitter release and contribute to synaptic dysfunction
and/or neurodegeneration, leading to dementia in AD. A view of AD pathogenesis
that encompasses both the amyloid-dependent and -independent mechanisms will
help fill the gaps in our knowledge and reconcile the findings that cannot be
explained solely by the amyloid hypothesis.
--------------------------------------------------------------------------------
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that begins
as mild short-term memory deficits and culminates in total loss of cognition and
executive functions. Currently, the precise cause of the disease is not known
and there is no cure. Genetic studies (Price et al., 1998) have identified
mutations in amyloid precursor protein (APP) and presenilin 1 and 2 (PS1, PS2)
that cause rare, dominantly inherited familial AD (FAD). Proteolytic processing
of APP by BACE (β-site APP cleaving enzyme) followed by PS-containing
γ-secretase complex generates amyloid-β (Aβ) peptides that deposit in amyloid
plaques. Genetic and cell biological studies show increased production of more
amyloidogenic Aβ peptides associated with FAD-linked mutations, providing strong
support for the amyloid hypothesis (Hardy and Selkoe, 2002), which posits that
Aβ peptides play a pivotal role in AD pathogenesis. However, Aβ peptides are
also generated as a part of normal metabolism and there is no consensus
regarding the identity of the disease-causing, pathological form of Aβ.
Despite the genetic and cell biological evidence that supports the amyloid
hypothesis, it is becoming clear that AD etiology is complex and that Aβ alone
is unable to account for all aspects of AD (Pimplikar, 2009). For example,
recent neuroimaging studies confirm the previous autopsy findings that amyloid
deposits are present in cognitively normal individuals, whereas some AD patients
show no amyloid deposits in PET (positron emission tomography) scans (Edison et
al., 2007; Li et al., 2008). Similarly, it is possible that all of the
amyloid-focused clinical trials failed because they were started too late in the
disease progression, but the negative outcome is also consistent with the notion
that AD can be caused by Aβ/amyloid-independent factors. The fact that vast
overproduction of Aβ peptides in the mouse brain failed to cause
neurodegeneration raises further questions as to whether accumulation of Aβ
peptides is indeed the culprit for neurodegeneration in AD. Also, a large number
of preclinical studies support roles for calcium dysregulation, proteolysis
failure, altered cell signaling, oxidative stress and inflammation in neuronal
dysfunction, and neurodegeneration similar to those observed in AD. This article
highlights the findings that were presented in a symposium and is not meant to
be a comprehensive review of AD pathogenesis. Here we discuss studies showing
that mutations in APP and presenilins can contribute to AD pathology by
amyloid-independent mechanisms.
FAD MUTATIONS IN APP AND PS1 LEAD TO DEFECTIVE ENDO-LYSOSOMAL TRAFFICKING AND
PROTEOLYSIS
The lysosomal network, comprising the endocytic and autophagic pathways,
mediates the processing, sorting, and turnover of proteins and other cellular
constituents. Endocytosis is especially critical in neurons, as it supports such
specialized functions as synaptic transmission and retrograde trophic signaling
(Nixon et al., 2008). Autophagy, the principal degradative pathway for
organelles and long-lived proteins, involves the sequestration of cytoplasmic
constituents within autophagosomes followed by digestion of these substrates
within autolysosomes that are formed by fusion of autophagosomes with lysosomes.
Autophagy is essential for neuronal survival in part by clearing damaged,
aggregated, or obsolete proteins in disease states and cellular aging (Wong and
Cuervo, 2010). Notably, longevity and cellular aging mechanisms are closely
linked to the efficacy of autophagy (Madeo et al., 2010), and during aging, a
sine qua non for the development of Alzheimer's disease, autophagy efficiency
declines (Cuervo, 2008). The neuron's unique reliance on the lysosomal system is
well documented in many primary lysosomal disorders where the defect in a
ubiquitous lysosomal protein produces severe neurodegenerative phenotypes
(Bellettato and Scarpa, 2010), including pathologies characteristic of AD (Ohm
et al., 2003; Ohmi et al., 2009). The close connection between neurodegeneration
and lysosomal system dysfunction is further highlighted by the growing numbers
of lysosomal system proteins identified as pathogenic in familial late-onset
neurodegenerative disorders, including forms of Parkinson's disease (McCray and
Taylor, 2008; Nixon et al., 2008; Cherra et al., 2010).
Recent evidence shows that mutations of PS1 and APP (or APP gene duplication),
independently of Aβ, directly disrupt autophagy or alter endocytosis, which
impairs neuronal function and reduces neuron survival (Fig. 1). PS1 has recently
been found to be essential for lysosomal proteolysis and autophagy by enabling
the acidification of lysosomes required for protease activation (Lee et al.,
2010). In PS1-lacking neurons, vacuolar ATPase (vATPase), the proton pump that
acidifies lysosomes, is not delivered to lysosomes. Failed lysosome
acidification blocks substrate proteolysis during autophagy, causing
incompletely degraded proteins to accumulate in autolysosomes. The underlying
mechanism involves a novel role for PS1, independent of γ-secretase, in which
PS1 holoprotein, before being cleaved and assembled into γ-secretase,
facilitates N-glycosylation of the V01A subunit of vATPase in the endoplasmic
reticulum, which is required for its efficient delivery to lysosomes and for
assembly of the proton pump. In familial early-onset AD, PS1 mutations lead to a
similar loss of lysosome function by the same mechanism (Lee et al., 2010), most
likely resulting from a dominant-negative effect of mutant PS1. Deficient
lysosomal proteolysis leads to the extensive “neuritic dystrophy” of AD (Suzuki
and Terry, 1967; Masliah et al., 1993) characterized by grossly swollen neurites
packed with autophagic vacuoles containing Aβ and other incompletely degraded
substrates (Nixon et al., 2005; Yu et al., 2005) that are potentially neurotoxic
(Yang et al., 2008). This massive “storage” of waste proteins, reminiscent of
lysosomal storage diseases, can be experimentally reproduced in neurons by
inhibiting lysosomal cathepsin proteolysis (Boland et al., 2008). Interestingly,
impaired autophagy in the AD brain results in Aβ accumulation in autolysosomes,
and this reservoir of intracellular Aβ may exert further toxicity to the
lysosome system (Glabe, 2001). Experimental measures may stimulate autophagy
restore lysosomal proteolysis to more normal levels have yielded promising
therapeutic effects on neuronal function and cognitive performance in mouse
models of AD (Sun et al., 2008; Spilman et al., 2010) and in certain other
neurodegenerative diseases (García-Arencibia et al., 2010).
FIGURE 1.
Open in a new tab
Dysfunction of autophagic and endocytic pathways to lysosomes driven by relevant
genes and other risk factors in Alzheimer's disease. A–C, A normal neuron is
depicted in A. At the earliest stages of AD (B), an abnormal acceleration of
endocytosis, mediated partly by rab5, is known to be caused by App gene
duplication (via β-CTF) in early onset FAD and Down syndrome and promoted by
ApoE4 and elevated cholesterol in late-onset AD. Adverse consequences include
endosome enlargement and defective endosome retrograde transport and
neurotrophin signaling functions, which promote apoptotic pathway activation and
neurodegeneration, particularly of cholinergic neuronal populations.
Subsequently (C), failure of autophagy, prominently involving impaired lysosomal
proteolysis, leads to massive selective accumulation of autophagic vacuoles
(autophagosomes, autolysosomes etc,) containing partially digested autophagic
and endocytic substrates within swollen “dystrophic” neurites. The diminished
clearance by autophagy of toxic organelles and proteins, including Aβ,
ubiquitinated proteins, activated caspases, and possibly tau, leads to
neurodegeneration via multiple pathways. Failure of lysosomal proteolysis and
autophagy in AD is driven directly by PS1 mutations in early-onset FAD, and is
also promoted by normal aging, oxidative stress, Apo E4, intracellular Aβ, and
other AD-related genetic and environmental risk factors.
Autophagy deficits in AD are part of a continuum of lysosomal system deficits,
including endocytic abnormalities that may be manifested as the first specific
signs of AD (Cataldo et al., 2000; Jiang et al., 2010; Rothenberg et al., 2010)
(Fig. 1). Abnormal acceleration of neuronal endocytosis is evident before
amyloid is deposited in the neocortex (Cataldo et al., 1997, 2000). Genes
related to endocytosis, such as Rab5, Rab7, and Rab4, are among the first group
to be upregulated in AD (Ginsberg et al., 2010) and are abnormally recruited to
endosomes, which progressively enlarge. This pattern is specific for AD among
studied aging-related neurodegenerative diseases and is accelerated by
inheritance of the ε4 allele of APOE (apolipoprotein E), the major genetic risk
factor for late-onset AD (Cataldo et al., 2000). In a form of AD caused by App
gene duplication and in Down syndrome, where a chromosome 21 segment containing
App is trisomic, endosome dysfunction can be attributed to the extra copy of App
(Cataldo et al., 2003; Salehi et al., 2006; Jiang et al., 2010) and has been
linked to altered trophic signaling and cholinergic neurodegeneration (Salehi et
al., 2006), and activation of apoptotic pathway (Neve et al., 1996). Recently,
these effects of increased App dosage were shown to be mediated specifically by
the β-cleaved C-terminal fragment of APP (Jiang et al., 2010), previously known
to have neurotoxic properties relevant to AD (Oster-Granite et al., 1996; Kim et
al., 2000; Choi et al., 2001; Mathews et al., 2002; Arbel et al., 2005; Lee et
al., 2006).
FAD MUTATIONS IN APP AND PS1 CAN EXERT DELETERIOUS EFFECTS INDEPENDENT OF AΒ
It has been proposed that PS FAD mutations promote neurodegeneration by
increasing neurotoxic peptide Aβ42. More recent work, however, shows that many
FAD mutants increase neither production of Αβ42 nor the Aβ42/40 ratio that has
been thought to initiate AD pathology (Bentahir et al., 2006; Shioi et al.,
2007; Batelli et al., 2008). Also, the Swedish mutation of APP increases
production of both Aβ42 and Aβ40 but does not change the ratio (Duering et al.,
2005). Thus, although some FAD mutations increase Aβ42 and/or the Aβ42/40 ratio,
not all mutations show this phenomenon. Furthermore, Aβ peptides are normal
components of human serum and CSF, and there is little evidence that Aβ is
neurotoxic at in vivo concentrations, which are severalfold lower than the
concentrations Aβ is used in in vitro neurotoxicity assays (for review, see
Robakis, 2010).
Currently more than 30 FAD mutations have been mapped on the APP gene. Some of
these mutations do not change the primary sequence of Aβ while others fall
within the Aβ region. A mutation within this region, Glu693Gln, does not
increase Aβ production but increases its tendency to form amyloid. Carriers of
this mutation develop the fatal syndrome of hereditary cerebral hemorrhage with
amyloidosis of Dutch type (HCHWA-D), characterized by recurrent cerebral
hemorrhages due to accumulation of amyloid depositions in cerebral blood
vessels. These patients are not classified as AD as they are usually not
demented. Other APP mutations on residues 692 and 694, however, are associated
with FAD, but these increase neither Aβ production nor the 42/40 ratio.
Interestingly, APP mutations of the London type, which cause relatively small
increases in Aβ, induce AD at earlier ages than the Swedish mutation, which
causes much higher increases in Aβ than the London mutations. It should be noted
that in APP-based mouse models of AD, all products of APP metabolism are
increased together with Aβ, and there is evidence that some of these non-Aβ
products are neurotoxic (Nalbantoglu et al., 1997; Ghosal et al., 2009; Nikolaev
et al., 2009). Thus, behavioral abnormalities of animal models overexpressing
APP need to be interpreted with caution, as in addition to Aβ, other APP
metabolites may influence the final outcome and contribute to the mechanism(s)
of neurodegeneration (Robakis, 2010).
Indeed, as seen above in the case of vacuolar ATPase, there is ample evidence to
indicate that PS1 performs γ-secretase-independent functions in addition to its
role as a catalytic subunit of the γ-secretase complex. In addition to its role
in regulating calcium homeostasis, wild-type PS1 also stimulates the
phosphoinositide 3-kinase (PI3K)/Akt and MEK/ERK (MAP kinase
kinase/extracellular signal-regulated protein kinase) signaling pathways and
promotes cell survival and growth. By contrast, a number of PS1 FAD mutations
fail to stimulate the cell survival pathways and interfere with
γ-secretase-independent functions. These observations reveal the presence of
additional mechanisms by which FAD mutations in PS1 may promote
neurodegeneration and tau hyperphosphorylation (Baki et al., 2004, 2008; Kang et
al., 2005; Tu et al., 2006; Dreses-Werringloer et al., 2008).
Recent data show that in addition to the γ-cleavage of APP, the PS1–secretase
complex promotes the ε-cleavage of other transmembrane proteins, including
Notch1 receptor, cadherins, APP, and EphB receptors. This cleavage takes place
downstream from the γ-cleavages site resulting in the release of soluble
cytosolic peptides containing the intracellular C-terminal fragments (CTFs).
Several of these peptides, including APP intracellular domain (AICD), migrate to
the nucleus and regulate gene expression (Cao and Sudhof, 2001; Gao and
Pimplikar, 2001), while others remain in the cytoplasm where they regulate
stability of transcription factors (Kopan and Ilagan, 2004; Marambaud and
Robakis, 2005). Interestingly, γ-cleaved AICD fragment has been shown to exert
deleterious effects and recapitulate multiple AD pathological features in a
mouse model (Ryan and Pimplikar, 2005; Ghosal et al., 2009, 2010; Vogt et al.,
2009), and peptide EphB2/CTF2 generated by the ε-cleavage of EphB2 receptor
stimulates phosphorylation of NMDA receptor subunit NR2B (Xu et al., 2009).
Recent data show that in contrast to the proposed gain of function, PS1 FAD
mutations may inhibit the cleavage of proteins including APP, cadherins,
ephrinB, Notch1, and EphB receptors, leading to reduced production of the
corresponding CTF peptides (Song et al., 1999; Marambaud et al., 2003; Wiley et
al., 2005; Georgakopoulos et al., 2006; Litterst et al., 2007). These data raise
the possibility (Fig. 2) that FAD mutations promote neurodegeneration by
altering the production of peptides with important transcriptional and signal
transduction properties (Robakis, 2003).
FIGURE 2.
Open in a new tab
The ε-cleavage of receptors is mediated by γ-secretase and inhibited by PS FAD
mutations. This cleavage produces biologically active peptides containing the
CTFs of substrates. ε-cleavages can be stimulated by ligand binding or calcium
influx (Litterst et al., 2007). CTFs can travel to nucleus where they can
regulate gene expression or sequester transcription factors (TF) in the
cytoplasm. Many PS1 FAD mutants inhibit the ε-cleavage indicating FAD mutations
cause a loss of γ-secretase function (Marambaud et al., 2003). PM, Plasma
membrane; RE, response element.
The autosomal-dominant mode of FAD transmission is consistent with the notion
that these mutations cause gain of a toxic function. However, there is a
possibility that some FAD mutations in PS1 may function through allelic
interference. Evidence that PS1 FAD mutants inhibit the γ-secretase-catalyzed
ε-cleavages of many substrates (loss of function, see above), combined with
absence of FAD haploinsufficiency mutants, raises the possibility of a model of
allelic interference in which products of inactive FAD mutant alleles of PS
promote autosomal-dominant neurodegeneration by also inhibiting the functions of
the wild-type protein (Robakis, 2010).
SYNAPTIC DYSFUNCTION AND NEURONAL DEGENERATION CAUSED BY LOSS OF PS
The presenilin genes harbor most of the FAD-linked mutations and are highly
expressed in pyramidal neurons of the adult cerebral cortex, where AD
pathogenesis manifests. Analysis of viable presenilin conditional knock-out
mice, in which presenilin expression is selectively inactivated in excitatory
pyramidal neurons of the postnatal forebrain, revealed important PS functions
relevant to AD pathogenesis (Yu et al., 2001; Saura et al., 2004). Specifically,
loss of presenilins affects both short- and long-term plasticity, in the absence
of neurodegeneration. Furthermore, NMDA receptor-mediated responses are impaired
and synaptic levels of NMDA receptor subunits are reduced in the absence of PS.
Interestingly, loss of PS reduces levels of cAMP response element-binding
protein (CREB)-binding protein (CBP) and transcription of CREB/CBP target genes
(Saura et al., 2004; Beglopoulos and Shen, 2006), even though it was
subsequently observed that CREB-mediated transcription is regulated indirectly
by PS (Watanabe et al., 2009). Strikingly, PS cDKO mice (conditional double
knock-out mice lacking both presenilins in the postnatal forebrain) develop in
an age-dependent manner synaptic, dendritic, and neuronal degeneration with
accompanying astrogliosis and hyperphosphorylation of tau, demonstrating an
essential role for PS in neuronal survival (Beglopoulos et al., 2004; Saura et
al., 2004; Wines-Samuelson et al., 2010). Specifically, while presenilins are
inactivated at 4 weeks of age postnatally in PS cDKO mice, significant increases
(∼8-fold, compared with control mice) of apoptotic cell death are first detected
at 2 months of age. However, this represents only ∼0.1% of cortical neurons that
are undergoing apoptosis; thus, the total cortical neuron number and volume are
not significantly altered at this age. By 4 months of age, ∼9% of cortical
neurons are lost in PS cDKO mice, followed by 18% and 24% neuronal loss at 6 and
9 months of age, respectively. Furthermore, presenilins appear to promote memory
and neuronal survival in a γ-secretase-dependent manner, as conditional
inactivation of nicastrin, another component of the γ-secretase complex, in the
adult cerebral cortex similarly resulted in progressive memory impairment and
neurodegeneration (Tabuchi et al., 2009). These in vivo findings and a large
number of reports on the effects of FAD-linked mutations in culture and in vitro
systems as well as in Caenorhabditis elegans raised the possibility that PS
mutations may cause dementia and neurodegeneration in AD via a partial
loss-of-function and dominant-negative mechanism (Shen and Kelleher, 2007).
Indeed, a recent report showed that pathogenic mutations in PS1, such as L435F,
could result in complete loss of γ-secretase activity (Heilig et al., 2010). The
later onset of the disease in AD patients carrying presenilin mutations,
compared with PS cDKO mouse models, can be explained by the fact that while FAD
mutations confer partial (or complete) loss of presenilin activity, only one of
the PS alleles is affected in FAD patients.
The fact that synaptic impairments precede progressive neurodegeneration
suggests that synaptic dysfunction caused by loss of PS function promotes
subsequent neuronal degeneration. The role of presenilins in the synapse was
elucidated by systematic genetic analysis through the restriction of presenilin
inactivation to hippocampal CA1 or CA3 neurons (Zhang et al., 2009). This
strategy permitted analysis of the effects of presenilin inactivation in either
presynaptic or postsynaptic neurons of the Schaeffer collateral pathway. It was
found that long-term potentiation (LTP) induced by theta burst stimulation is
decreased after presynaptic but not postsynaptic deletion of presenilins.
Moreover, presynaptic but not postsynaptic inactivation of presenilins impairs
short-term plasticity and synaptic facilitation, and the defects in synaptic
facilitation are dependent upon the frequency used for stimulation and the
external calcium concentration. The probability of evoked glutamate release,
measured by the decay curve of the open-channel NMDA receptor antagonist MK-801
[5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate)], is reduced by
presynaptic inactivation of presenilins. To explore further the involvement of
calcium in the presynaptic defects caused by loss of presenilins, both calcium
influx and efflux were evaluated, and it was found that the current–voltage
relationship of voltage-gated calcium current is normal in the absence of PS.
Strikingly, depletion of calcium internal stores by thapsigargin, a
noncompetitive SERCA (sarcoplasmic/endoplasmic reticulum calcium ATPase) calcium
pump, mimics and occludes the effects of presynaptic presenilin inactivation,
suggesting a defect in calcium influx underlying the presynaptic impairment.
Blockade of calcium release from ryanodine receptors using two independent
inhibitors had effects similar to those of thapsigargin, whereas blockers of IP3
receptors had no effect on presynaptic frequency facilitation. These findings
were further corroborated using dissociated PS-null hippocampal neuronal
cultures from postnatal pups, in which the requirement of presenilins in neural
development is circumvented. These cultured PS-null hippocampal neurons show
normal neuronal morphology and synaptic density and recapitulate the presynaptic
defects seen in acute hippocampal slices of CA3-PS cDKO mice, suggesting that
they are relevant experimental systems to assess calcium homeostasis directly.
Indeed, depolarization-induced calcium increases in the cytosol, which are
composed of both calcium influx and calcium-induced calcium release from
intracellular stores, are reduced in hippocampal neurons lacking both
presenilins. Furthermore, blockade of ryanodine receptors but not IP3 receptors
mimics and occludes the effects of presenilin inactivation.
Collectively, these genetic and electrophysiological studies demonstrated that
loss of presenilin function impairs LTP induction and glutamatergic
neurotransmitter release by a presynaptic mechanism (Fig. 3). These findings
raised the possibility that presynaptic mechanisms may play a primary role in AD
pathophysiology (Shen, 2010). In support of this hypothesis, presenilins are
localized to presynaptic terminals (Zhang et al., 2009) and APP C-terminal
fragments, precursors of Aβ, accumulate in presynaptic terminals of PS1 cKO mice
(Saura et al., 2005). A time course study to identify temporal development of
presynaptic and postsynaptic defects in forebrain-PS cDKO mice further revealed
that presynaptic defects, such as synaptic facilitation, occur at 5 weeks of
age, followed by postsynaptic defects, such as NMDA receptor-mediated responses,
at 6 weeks of age, providing additional support for the importance of
presynaptic roles played by presenilins (Zhang et al., 2010).
FIGURE 3.
Open in a new tab
A model depicting the role of presenilins in the regulation of neurotransmitter
release. Upon stimulation, calcium concentration at the presynaptic terminal is
drastically elevated due to calcium influx through VGCCs and calcium-induced
calcium release (CICR) from intracellular stores, which is mediated through both
ryanodine receptors and IP3 receptors. Loss of PS function in the presynaptic
terminal specifically disrupts ryanodine receptor-mediated Ca2+ release from the
ER store, thus reducing CICR and resulting in reduced increases of
calcium-induced by action potentials in the presynaptic terminal. This reduction
in calcium increases impairs the probability of neurotransmitter release, and
the decreased glutamate release causes LTP impairment in PS-deficient
presynaptic terminals. (Figure taken from supplementary information in Nature
460:632–636, 2009. Reprinted with permission.)
DNA DAMAGE BY ABERRANTLY ACTIVATED CYCLIN-DEPENDENT KINASE 5
Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase
that has important roles in various neuronal functions including brain
development, synaptogenesis, synaptic plasticity, and memory formation (Dhavan
and Tsai, 2001). Cdk5 is activated when bound to one of its two activators, p35
or p39, which have related primary sequences. Aberrant activation of Cdk5 can
occur through the proteolytic cleavage of p35 to p25 via calpain, a
calcium-dependent protease (Kusakawa et al., 2000; Lee et al., 2000; Nath et
al., 2000). Evidence for a role of Cdk5 in the pathogenesis of neurodegenerative
conditions has been accumulating over the last several years (Patrick et al.,
1999; Wang et al., 2003; Qu et al., 2007).
Cdk5 activity is increased in postmortem AD brains; this is likely due to
increased p25 levels found in AD brain tissues compared with age-matched control
brain tissues (Patrick et al., 1999). Levels of p25 are also increased in AD
mouse models, including the PS1-deficient and 5XFAD mice (Oakley et al., 2006).
In vitro, Aβ1-42 causes p25 production in primary dissociated neurons (Lee et
al., 2000). A forebrain-specific inducible p25 (CK-p25) transgenic mouse model
exhibits elevated Aβ1-42 peptide, neurodegeneration characterized by massive
neuronal and synaptic loss, tau-associated pathology, and learning and memory
impairments (Cruz et al., 2003; Fischer et al., 2005; Kim et al., 2008).
Inhibition of Cdk5 activity in transgenic p25 mice reduces Aβ1-42 production
suggesting that Aβ1-42 processing is regulated by the Cdk5/p25 complex (Wen et
al., 2008). Conversely, inhibition of Aβ generation by BACE1 loss of function in
the CK-p25 mice rescued the impairments in synaptic plasticity and memory
formation (L.H.T., unpublished observation). These results indicate that Aβ
plays a crucial role in neurodegeneration exhibited by the CK-p25 mice.
Furthermore, they hint at the possibility that p25 and Aβ collaborate to cause
neuronal death.
To decipher the cellular mechanism(s) that leads to neurodegeneration,
microarray gene expression profiling experiments were performed in CK-p25 mice
before the detection of astrogliosis and neuronal loss (Kim et al., 2008).
Surprisingly, two main classes of genes were profoundly upregulated in the brain
of CK-p25 mice compared with control mice. The first class is cellular proteins
known to participate in mitotic cell division including cyclins, mitotic Cdks,
proliferating cell nuclear antigen, and E2F. The second class is components of
the DNA damage response pathway, especially DNA double-stranded break, including
RAD51, ATM, and DNA polymerase ε. Indeed, reactivation of cell cycle genes and
DNA double-stranded break lesions were demonstrated in the hippocampal neurons
of CK-p25 mice before the onset of neurodegeneration indicating that these
events may cause neuronal loss. Reactivation of cell cycle genes has been
reported in postmortem AD patients. Preliminary data indicate that the numbers
of neurons with DNA double-stranded break are significantly increased in AD
brains (L.H.T., unpublished observations).
It was postulated that a common mechanism may underlie both cell cycle
reactivation and DNA double-stranded breaks, as the two events were largely
observed in the same neurons in CK-p25 mice. Histone deacetylase 1 (HDAC1) has
been shown to repress the expression of numerous cell cycle proteins by binding
to their upstream regulatory elements (Brehm et al., 1998; Stiegler et al.,
1998; Lagger et al., 2002; Rayman et al., 2002). In CK-p25 mice, HDAC1 activity
was downregulated, and its association with the genes encoding cell cycle
proteins as well as with chromatin was reduced. Furthermore, HDAC1 loss of
function caused DNA double-stranded breaks, reactivation of cell cycle genes,
and neuronal death. Conversely, HDAC1 gain of function ameliorated p25-induced
DNA damage and cell death. Thus, reduced HDAC1 activity resulting from p25
accumulation may contribute to several early events leading to
neurodegeneration.
In conclusion, we think that p25/Cdk5 concurrently exerts two parallel processes
within the neuron (Fig. 4). One aspect involves deficits in synaptic plasticity,
and learning and memory in which p25/Cdk5 leads to increased β-amyloid, which in
turn contributes to synaptic impairments and memory loss. Meanwhile, p25/Cdk5
also exerts nuclear activity, resulting in dysregulation of HDAC1. HDAC1 loss of
function causes the upregulation of cell cycle genes and DNA double-strand
breaks. These pathologies eventually lead to neuronal loss and
neurodegeneration. Our results suggest that p25 generation plays a very upstream
and critical role in the signaling cascade leading to neurodegeneration,
contributing to both cognitive symptoms and cellular demise. Thus, targeting
Cdk5 or p25 generation may provide new promising avenues for therapeutic
intervention of Alzheimer's disease.
FIGURE 4.
Open in a new tab
p25/Cdk5 in the pathogenesis of Alzheimer's disease. The p25/Cdk5 kinase exerts
two parallel processes in the course of neurodegeneration. First, it increases
β-amyloid production which contributes to synaptic impairment and memory loss.
Second, p25/Cdk5 in the nucleus reduces HDAC1 activity, which leads to increased
expression of cell cycle genes and DNA double-strand breaks. These pathologies
eventually lead to neuronal loss and neurodegeneration. DSBs, double-strand
breaks.
CONCLUDING REMARKS
Today, research in the field of AD is on the precipice of a crucial and somewhat
paradoxical juncture. On the one hand, progress made in multiple fields of
investigation (genetics, biochemistry, cell biology, epidemiology, neuroimaging,
etc.) has yielded tremendous insights into the possible cause of AD, and we are
closer to finding a disease-modifying treatment. On the other hand, it has
become increasingly clear that disproportionate reliance on Aβ/amyloid-based
mechanisms to explain AD etiology and nearly exclusive emphasis on amyloid as a
therapeutic target have not yielded the desired results. Genetic studies of FAD,
which accounts for ∼3–5% of AD cases, have been considered the strongest
evidence supporting the amyloid hypothesis; however, as discussed above, there
is increasing evidence that even the FAD mutations in APP and presenilins can
act via amyloid-independent mechanisms. Indeed, it is clear from the data
discussed above that the amyloid-dependent and amyloid-independent mechanisms
are not mutually exclusive and both can contribute to AD pathology.
An important challenge for future studies will be to determine the extent to
which amyloid-independent mechanisms contribute to AD. The implicit assumption
underlying the current drug trials is that the prime causative agent of AD is
amyloid/Aβ-peptides, and therefore that blocking amyloid accumulation will
prevent AD. However, if amyloid-independent mechanisms also make significant
contributions to AD, then the current drug trials will yield only moderately
positive results, as the case has been. Another challenge facing future
investigations will be to produce a satisfactory explanation as to why AD takes
so long to manifest itself and why certain parts of the brain (limbic system)
are more susceptible in AD. As future studies seek answers to these questions,
it is becoming clear that both amyloid-dependent and amyloid-independent
mechanisms (Fig. 5) are involved in contributing to AD pathology and that an
effective disease-modifying treatment will arise only from a strategy that
addresses both of these mechanisms.
FIGURE 5.
Open in a new tab
AD-360°. This global view of AD pathogenesis includes both the
amyloid-independent (green pathway) and amyloid-dependent (red pathway)
mechanisms. The Aβ/amyloid-independent mechanisms are mediated via APP,
intracellular fragments (i-CTFs) and PS1 via the cellular processes discussed
here (green arrows) while the amyloid mechanisms are mediated via Aβ42 or Aβ
oligomers or plaques (red arrows). Cdk5 (blue box) may be influenced by or
interacts with both pathways and its activation triggers DNA damage, cell cycle
activation and neurodegeneration (blue arrows). Non-APP/PS factors such as Tau
and ApoE also contribute to AD pathology (blue and black arrows) and there is
strong evidence to suggest that cellular processes such as inflammation,
oxidative stress and Ca2+ dysregulation implicated in AD pathogenesis can be
triggered by both amyloid-dependent and amyloid-independent mechanisms. All of
these pathways can lead to synaptic dysfunction and neurodegeneration and AD
most likely results from the cumulative effects of multiple pathway.
FOOTNOTES
These studies were supported by National Institutes of Health Grants
R01-AG026146 (S.W.P.), P01-AG17617 (R.A.N.), AG008200 and R37 AG017926 (N.K.R.),
R01-NS041783 and R01-NS042818 (J.S.), and P01-AG027916 and R01-NS051874
(L.-H.T.). S.W.P., R.A.N., and J.S. also acknowledge funding from the
Alzheimer's Association. We thank Dr. Chris Nelson for editing the manuscript.
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