the number of neurons in the human brain approximates the number of stars in the galaxy . the result is an incredibly complex and sophisticated network made of roughly 100 trillion synapses . communications between neurons in the brain occur primarily through synapses formed between presynaptic and postsynaptic partners . for fast synaptic transmission , there are two types of synapses : type i synapses use glutamate as the neurotransmitter and are excitatory , whereas type ii synapses use gamma - amino butyric acid ( gaba ) as the major neurotransmitter and are inhibitory . while dendritic shafts are the main location for the inhibitory gabaergic synapses , dendritic spines , which are small membrane protrusions from dendritic shafts that contain glutamate receptors and postsynaptic density components , are the primary locations of excitatory synapses . a functional balance between neuronal excitation and inhibition is established during development for homeostatic control of neuronal excitability and is maintained into adulthood [ 14 ] . on the other hand , imbalances between neuronal excitation and inhibition have been associated with many neurological disorders including epilepsy , schizophrenia , fragile x syndrome , and autism . information can be stored in the brain by multiple synaptic mechanisms , including altered structure and chemistry of existing synapses , formation of new synapses , or elimination of old ones . such synaptic plasticity is thought to be fundamental to learning and memory in the brain . at the electrophysiological level , synaptic plasticity is reflected in processes known as long - term potentiation ( ltp ) and long - term depression ( ltd ) . excitatory synapses contain ampa and nmda ionotropic glutamate receptors localized on dendritic spines , with basal synaptic transmission largely mediated by the ampa receptors . high synaptic activity opens nmda receptors , leading to long - lasting changes in postsynaptic ampa receptor number and ltp of synaptic transmission . alternatively , low levels of synaptic stimulation can activate nmda receptors to produce ltd . at the morphological level , ltp is generally associated with dendritic spine growth , whereas ltd can induce the removal of postsynaptic ampa receptors and loss of spines [ 1319 ] . it is thus not surprising that synaptic development , maintenance , and plasticity under normal physiological conditions are frequently associated with changes in the morphology and number of dendritic spines .   in many neurodegenerative diseases , particularly those exhibiting cognitive impairments such as alzheimer 's disease ( ad ) and parkinson 's disease ( pd ) , changes in dendritic spine number and morphology are also found in other disease conditions such as autism , down syndrome , drug addiction , fragile x syndrome , and schizophrenia [ 2024 ] . it is worth emphasizing that degeneration of synapses and dendritic spines is one of the earliest features in those neurodegenerative disease conditions , prior to subsequent loss of neurons . interventions aimed to protect the nervous system from the ravages of these disease would therefore seem more effective when the synaptic and spine pathology are prevented as early as possible .   in this review article , we will summarize recent advances in our understanding of the molecular mechanisms underlying synaptic and dendritic spine pathology in neurodegenerative diseases , particularly in ad and pd . the readers are referred to some excellent previous reviews on the observation of synaptic and dendritic spine pathology in neurological disorders [ 2225 ] . ad is the most common neurodegenerative disease and the leading cause of dementia in the elderly . decades of intensive research have uncovered amyloid plaque and neurofibrillary tangle ( nft ) as the pathological hallmarks , and soluble amyloid- ( a ) oligomers as the leading candidate for the causative agent of ad [ 26 , 27 ] . however , the mechanistic link between amyloid plaque and nft and the mechanism by which a oligomer may cause cognitive impairments remains poorly defined , and there is no effective treatment for this devastating disease . substantial evidences have accumulated indicating that the memory deficits in ad patients do not correlate well with amyloid plaque burden ; instead , the loss of synaptic markers is a better predictor of clinical symptoms and disease progression . together with studies using animal ad models , these studies have lent support to the hypothesis that ad could be conceptualized as a disease of synaptic failure . early structural studies of postmortem tissues showed that when compared with age - matched control brains , ad brains had reduced synapse density and number of dendritic spines in the cortex and hippocampus , principal brain areas affected by the disease , and that greater loss of dendritic spines was associated with lower mental status [ 29 , 30 ] . these findings suggested that progressive loss of dendritic spines is directly related to the pathogenesis of ad and represents a good indicator of disease progression . studies of transgenic mouse models of ad have shown that , in the vicinity of amyloid plaques , there were dramatic spine loss and neurite dystrophy , structural changes that could lead to altered neuronal circuits and brain functions [ 3133 ] . further studies showed that the accumulation of soluble a might be the culprit that leads to dendritic spines loss . a is the proteolytic product of a large protein called amyloid precursor protein ( app ) , which is cleaved by beta- and gamma - secretases to produce a and other fragments of the precursor protein . interestingly , the formation and secretion of a peptides are positively regulated by neuronal activity , and excess a peptide can in turn depress excitatory synaptic transmission onto neurons that produce a as well as nearby neurons that do not produce a . thus , activity - dependent modulation of a production may normally participate in a negative feedback regulatory loop to restrain neuronal hyperactivity , the impairment of which could contribute to ad pathogenesis . under normal conditions , a monomers could be cleared by proteolytic enzymes like neprilysin , chaperone molecule apoe , or the lysosomal and proteasomal pathways . however , under pathological conditions , soluble a levels are increased , leading to the buildup of a oligomers , which can be further sequestered into protofibrils and fibrils as seen in plaques . first , genetic studies of familial forms of ad have identified rare genetic mutations that cause ad by altering the production or metabolism of a peptides , leading to their aberrant accumulation [ 27 , 37 ] . soluble a levels have been found to better correlate with disease progression and severity than amyloid plaques or nfts . second , a oligomers formed in vitro from synthetic peptides , purified from cultured cells expressing app , or from cortex of ad patient brains can induce synaptic dysfunction and neuritic degeneration [ 3841 ] . third , the reduction of soluble a levels using an immunization method in mouse ad models rescued the cognitive deficits . however , despite the overwhelming supporting evidences , the a hypothesis of ad as described above still faces challenge , since several highly publicized clinical trials targeting a had failed . the molecular mechanisms through which a might cause synaptic loss and neuronal death remain uncertain . a has been found to form pore - like structures with calcium channel activity , which could interfere with calcium signaling [ 43 , 44 ] . a can also affect ltp and ltd by modulating glutamate receptor - dependent signaling pathways [ 4547 ] and trigger aberrant patterns of neural network activity . one of the earliest clues about the mechanisms of a-induced synaptic dysfunction came from studies of cultured neurons derived from tg2576 mutant app transgenic mice . among the synaptic changes observed were fewer and smaller postsynaptic compartments and fewer and enlarged active presynaptic compartments notably , the earliest observable change in synaptic components was the reduction of psd-95 , which is a master regulator of the assembly and anchoring of postsynaptic density components such as glutamate receptor subunits . a was shown to be the toxic agent causing these synaptic changes since the effects were blocked by gamma - secretase inhibitor treatment and recapitulated by application of synthetic a to wild - type neurons . studies in drosophila models showed that par-1 kinase , the fly homologue of mammalian microtubule affinity regulating kinases ( marks ) , can directly phosphorylate the fly psd-95 homologue dlg , and this phosphorylation event caused the delocalization of dlg from the postsynaptic membrane . par-1/mark kinases are known to be activated by app or a in drosophila or mammalian neurons [ 55 , 56 ] . it would be interesting to test whether marks are critical mediators of a toxicity on mammalian synapses and dendritic spines . a significant recent advance in our understanding of the mechanisms of the synaptic toxicity of a has been the finding that a uses ltd - related signaling mechanisms to affect synaptic function and dendritic spine morphology . one of the principle mechanisms of ltd induction is the removal of ampa receptors from the postsynaptic membrane through endocytosis . overexpression of a resulted in decreased spine density and postsynaptic ampa receptor number , through signaling molecules implicated in ltd , such as p38 map kinase and calcineurin . importantly , expression of a mutant form of ampa receptor that resists ltd - driven endocytosis blocked the morphological effects and synaptic depression induced by a . this study implicated the endocytosis of ampa receptors as a major mechanism through which a causes synaptic dysfunction and subsequent degeneration , but the detailed molecular mechanisms remain unclear . recent studies using transgenic mouse models of ad have implicated the microtubule - binding protein tau as a major mediator of the toxicity of a at the postsynaptic compartment and dendritic spines . although tau abnormality has long been observed in ad , as exemplified by the formation of nfts by tau that accompany plaque pathology , and tau abnormality can cause neurodegeneration in the absence of plaque pathology as in frontotemporal dementia cases [ 57 , 58 ] , the direct involvement of tau in a-induced synaptic and dendritic spine pathology may initially appear surprising , since tau is generally considered a presynaptic protein that is primarily localized to axons . in fact , the relationship between nfts and amyloid plaques in disease pathogenesis has long been a source of considerable debate [ 37 , 59 , 60 ] . studies in mice suggested that the two lesions might be causally linked . in transgenic mouse models , intracranial injection of synthetic a , or crossing of app transgenic mice with tau transgenic mice , promoted nft pathology [ 6163 ] , and immunization of app / psn / tau triple transgenic mice with antibodies against a reduced the levels of hyperphosphorylated tau . this was consistent with earlier studies showing that the removal of tau could relieve a-induced neurotoxicity in cultured neurons . together , these studies support the notion that the initiating event in ad is the accumulation of the toxic a peptides , and that tau abnormality is a major downstream molecular event that contributes to disease pathogenesis . previous studies have shown that a could lead to abnormal activation of a number of kinases , including cyclin - dependent kinase-5 ( cdk5 ) [ 66 , 67 ] , fyn kinase [ 68 , 69 ] , glycogen synthase kinase-3beta ( gsk3 ) , and mark [ 7173 ] , all of which promote tau hyperphosphorylation and could potentially affect synaptic structure and function . however , very few in vivo studies have been done to assess the roles of tau kinases or phosphatases in conferring tau toxicity and in causing ad - related memory deficit . recently studies have shown that removing endogenous tau can prevent a-induced behavioral deficits in a mouse ad model expressing human app , and block excitotoxin - induced neuronal dysfunction in both transgenic and nontransgenic mice . since current data support postsynaptic toxicity as a primary mechanism of a action in causing learning and memory deficits in ad , this study raised the possibility that tau may also act in the postsynaptic compartment . indeed , under both physiological and pathological conditions , tau was found in dendrites [ 75 , 76 ] , albeit the level of dendritic tau was much higher under disease conditions . tau was known to interact with microtubules through its microtubule - binding domain to stabilize microtubule and regulate axonal transport . it has many putative phosphorylation sites and becomes hyperphosphorylated in ad patients and transgenic animal models [ 57 , 58 ] . apart from the notion that phosphorylation can lead to the dissociation of tau from the microtubules , other pathophysiological effects of this molecular event are unknown . a recent study has indicated that phosphorylated tau could accumulate in dendritic spines , where it may affect the synaptic trafficking and/or anchoring of glutamate receptors , thereby influencing postsynaptic function . interestingly , this effect of tau on synaptic function occurred without causing the loss of synapses or dendritic spines . this study thus revealed a critical role for tau phosphorylation in causing tau mislocalization and subsequent synaptic impairment , and it established dendritic spines as pathogenic targets of tau action . tau interacts with fyn , a protein tyrosine kinase that can phosphorylate tau and whose activity is increased in ad brain . ittner et al . showed that the interaction of tau with fyn leads to the targeting of fyn to dendritic spines , where fyn can phosphorylate nmda receptor subunit 2 ( glur2 ) , resulting in stabilization of the interaction between glur2 and psd-95 and enhanced excitotoxicity . tau also shows strong interaction with psd-95 , providing further support for a dendritic role of tau besides its known axonal function . importantly , the toxic effects of app / a were attenuated by interfering with glur2/psd-95 interaction with a cell - permeable peptide , supporting that dendritic tau - mediated fyn recruitment and glur2/psd-95 interaction confer a toxicity at the postsynapse . thus , a  tau hypothesis  has been put forward based on these recent results ; a triggers the phosphorylation of tau , causing tau to dissociate from the microtubules and accumulate at the dendritic compartments . phosphorylated tau exhibits stronger interaction with fyn and thus facilitates the targeting of fyn to dendritic spines . the targeting of fyn to postsynaptic density sensitizes the nmda receptors and renders neurons more vulnerable to the toxicity of a in the postsynaptic compartment . it remains to be determined whether tau becomes hyperphosphorylated in situ in the dendritic spines as a result of altered kinase / phosphatase activities there , or that it becomes hyperphosphorylated elsewhere and is then transported to the dendritic spines . nevertheless , targeting the tau - dependent pathway , for example , by reducing tau protein level , inhibiting tau kinase activities , or increasing phosphatase activities , would represent suitable new ways of treating ad .   in summary , we can consider the toxic effect of a on neuronal synapses and dendritic spines as a normal physiological process gone awry , instead of some pathological process unique to the disease process . a is continuously produced in the brain , and its production can be stimulated by neuronal activity . a can then feedback on the hyperactive neuron using a ltd - related mechanism to tune down neuronal activity , for example , by promoting ampar removal . this process normally acts as a homeostatic mechanism to restrain neuronal hyperactivation . in the disease process , however , the buildup of a tips the balance of this process toward excessive synaptic depression and ampar removal , resulting in synapse and spine loss ( figure 1 ) . the molecular mechanisms involved in a toxicity on synapses and dendritic spines are just beginning to be elucidated . we propose that a signaling cascade from a to tau and psd-95 , involving tau kinases such as par-1/mark and its activating kinase lkb1 , might be involved ( figure 1 ) . although much of the research on the mechanisms of a toxicity to synapses and spines has taken a approach , it is worth noting that other nonneuronal cell types in the brain play critical roles in the formation and maturation of synapses during development , and similar mechanisms may operate in the adult brain to mediate the effects of a on neuronal synapses and dendritic spines .   besides providing trophic factors for neurons , glial cells have been shown to play key roles in regulating neuronal migration , axon guidance , and synapse formation . in one of the better - characterized cases , astrocytes were shown to secret signals that induce synapse formation by retinal ganglion cells ( rgcs ) . a family of extracellular matrix proteins called thrombospondins ( tsps ) was identified as the synaptogenic signals coming from astrocytes . the tsp receptor from the neuronal side involved in synaptogenesis was found to be the calcium channel subunit 2-1 . interestingly , the synapses formed by tsps are postsynaptically silent due to the lack of surface ampa receptors , whereas those formed by astrocyte conditioned medium are postsynaptically active , suggesting that additional factors are secreted by the astrocytes to control synaptic strength and plasticity . also , synapses are made in excess during development , and the extra synapses or weak synapses are eliminated by a process involving signals from astrocytes that induce the classical complement pathway protein c1q in neurons . in addition to secreted factors , astrocytes can regulate synapse formation using contact - mediated mechanisms . astrocytes also regulate dendritic spine morphology through a contact - mediated mechanism involving bidirectional ephrin / epha signaling . in the hippocampus , for example , astrocytes express ephrin a3 , whereas neurons express the ephrin receptor epha4 . perturbing ephrin / epha signaling results in defects in spine formation and maturation . one can imagine that disruption of astrocyte - neuron interaction by a could affect synapse and spine morphology through the above - mentioned mechanisms . in this respect , it is interesting to note that a recent study has shown that lentiviral - mediated delivery of ephb2 expression constructs in the dentate gyrus of happ transgenic mice reversed deficits in nmda receptor - dependent ltp and memory impairments . whether there is the other abundant glial cells in the brain are microglia . unlike the astrocytes , these cells are of mesodermal origin . the roles of microglia in disease pathogenesis in ad and other neurodegenerative diseases are very complex and controversial [ 87 , 88 ] . this probably has to do with the diverse activities of these cells in the brain . relevant to ad pathogenesis , microglia can promote a clearance , release anti - inflammatory cytokines and neurotrophic factors on one hand , and they can also affect the activation of complement systems and elimination of synapses and spines on the other hand . thus microglia can exert neuroprotective as well as neurodegenerative effects , depending on the strength , timing , and duration of their activation . imaging studies showed that activated microglia were found in patients with mci , suggesting that neuroinflammation is an early event in the disease process . consistent with this finding , microglial activation was observed early in a tauopathy mouse model , preceding nft formation and roughly concurrent with synapse loss and impairment of synaptic function . interestingly , supplement of immunosuppressant fk506 to young mice attenuated tau pathology and increased lifespan , suggesting that microglia activation may contribute to disease . in another ad mouse model expressing the e693 mutation that causes ad by enhanced a oligomerization without fibrillization , it was found that the mice displayed age - dependent accumulation of intraneuronal a oligomers at around 8 months , when abnormal tau phosphorylation , and impairments of hippocampal synaptic plasticity and memory were observed . however , microglial activation was observed from 12 months , astrocyte activation from 18 months , and neuronal loss at 24 months . it is not known in this case whether microglial and astrocyte activation plays a neurodegenerative role or as part of a neuroprotective , compensatory response .   despite the large amount of literature documenting a detrimental role for microglia and astrocyte activation in the disease process , for example , microglia are proposed to play a surveillance role by constantly monitoring and sensing synaptic health , and , in addition to the critical roles , astrocytes play in synapse formation as mentioned earlier , and these cells can also control extracellular glutamate levels , remove excess extracellular k , release gliotransmitters , store glucose and transform it into lactate as energy source of neurons , and scavenge ros to protect against oxidative damages . given these essential roles of glia to neuronal function and health , it is possible that damaging of glial cells by a may have equally harmful effect on the neurons eventually . in fact , there is evidence that glial cells can release ros upon a exposure , and glial - released cytokines may even trigger a signaling process that promotes tau hyperphosphorylation . thus , a possible role of dysfunction glial cells in ad pathogenesis should be considered , especially in the early stages of the disease process ( figure 2 ) . synapse and dendritic spine pathology have been observed in the early stages of neurodegenerative diseases before neuronal death is evident , suggesting that these cellular locations represent pathogenic sites of action by the disease - causing agents early in the disease process . at least in the case of ad , there is compelling evidence supporting a pathogenic role for the synaptic and dendritic spine abnormalities . an intriguing possibility is that , as in ad , defects in the morphology and function of synapses and dendritic spines may play a critical role in the pathogenesis of pd . in fact , alterations in synaptic plasticity as represented by ltp and ltd are observed in pd , and some familial pd - associated genes have been shown to affect synapse and dendritic spine morphology and function [ 95 , 96 ] . it would thus be interesting to examine whether ltp- and ltd - related signaling mechanisms are involved in pink1/parkin - induced synapse and dendritic spine changes . in this respect , it would also be interesting to test the potential role of dendritic tau in mediating the synaptic effects of the fpd genes . this is particularly relevant , given the identification of tau as a susceptibility factor for pd . future studies along these directions could lead to the identification of common molecular mechanisms underlying the pathogenesis of ad , pd , and possibly other neurological disorders and offer new therapeutic strategies .