Autophagy in Dementias

Abstract

Dementias are a varied group of disorders typically associated with memory loss, impaired judgment and/or language and by symptoms affecting other cognitive and social abilities to a degree that interferes with daily functioning. Alzheimer’s disease (AD) is the most common cause of a progressive dementia, followed by dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), vascular dementia (VaD) and HIV associated neurocognitive disorders (HAND).

The pathogenesis of this group of disorders has been linked to the abnormal accumulation of proteins in the brains of affected individuals, which in turn has been related to deficits in protein clearance. Autophagy is a key cellular protein clearance pathway with proteolytic cleavage and degradation via the ubiquitin-proteasome pathway representing another important clearance mechanism. Alterations in the levels of autophagy and the proteins associated with the autophagocytic pathway have been reported in various types of dementias. This review will examine recent literature across these disorders and highlight a common theme of altered autophagy across the spectrum of the dementias.

Introduction

Neurodegenerative disorders of the aging population are clinically characterized by dementia and movement alterations; they affect over 10 million people in the US alone and represent the fifth most common cause of death for patients 65 and older (109). Dementia describes a group of symptoms affecting cognitive and social abilities severely enough to interfere with daily functioning. Dementia is usually associated with memory loss, impaired judgment and/or language (109).

Alzheimer’s disease (AD) is the most common cause of progressive dementia (33, 34), followed by dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), vascular dementia (VaD) and HIV-associated neurocognitive disorder (HAND).

Most neurological disorders with dementia are characterized by progressive accumulation of misfolded proteins resulting in degeneration of selective synaptic circuitries in the neocortex, limbic system and cortico-striato nigral pathways. While the progressive accumulation of Aβ and Tau oligomers has been identified as a central pathogenic event in AD associated with synaptic dysfunction (81, 175), accumulation of α-synuclein (α-syn) and formation of oligomers has been linked to the pathogenesis of Parkinson’s Disease (PD) (43, 59, 88, 89, 93).

The pathology of AD and PD overlap in a heterogeneous group of conditions designated as Lewy body disease (LBD) (3, 16, 99, 115, 117). While in patients with DLB the clinical presentation is of dementia followed by parkinsonism, in patients with PD with dementia (PDD) the initial signs are of parkinsonism followed by dementia (71, 72, 100, 116). In PDD and the less common form of DLB, α-syn pathology predominates in both brainstem and cortical regions. In the more common form of DLB the pathological features of both AD and PD are present. Aβ promotes α-syn aggregation and toxicity in vivo (108), and Aβ and α-syn might directly interact (103) to form hybrid channel like structures (164).

Other disorders with cognitive impairment falling under the umbrella of FTD (54, 77) are usually characterized by the accumulation of Tau (45) or TDP43 (19, 42, 50, 157). Interestingly, in older individuals with chronic HIV infection, in addition to the neuroinflammatory process, proteins such as Aβ (4, 49, 123), Tau (25, 44, 130) and α-syn (78) accumulate in a distinct pattern. These patients exhibit neurodegeneration and neurocognitive disorders that in more severe instances can result in dementia.

Alterations in the rate of: 1) synthesis, 2) aggregation and 3) clearance of these proteins might be responsible for the formation of toxic Aβ, α-syn and Tau oligomers in AD, DLB, FTD and HAND (27) (Figure 1). Genetic mutations in familial cases and polymorphisms and environmental factors have been linked to alterations in the biosynthesis, aggregation and clearance. Clearance mechanisms include proteolytic cleavage, binding to chaperones and degradation via the ubiquitin-proteasome or lysosomal pathways. Of the lysosomal pathways, autophagy has become one of the most widely investigated. Autophagy is the major pathway involved in the degradation of long-lived proteins and organelles, cellular remodeling, and survival during nutrient starvation (82, 95). There are three distinct autophagic pathways (29, 86): i) macroautophagy, ii) microautophagy and iii) chaperone-mediated autophagy (CMA) (Figure 2). Autophagy has been linked to neuronal cell survival, death (23, 39) and transformation. Macroautophagy is constitutively active and highly efficient in neurons under physiological and disease conditions.

Figure 1.

Protein accumulation and subsequent neurodegeneration can result from an imbalance between the rate of synthesis, aggregation and clearance of unwanted and misfolded proteins. Dysregulation of either of these systems may be responsible for the formation of toxic Aβ, α-syn and Tau oligomers in neurodegenerative disorders.

Figure 2.

Clearance of unwanted or misfolded proteins from cells occurs via the autophagy/lysosomal pathway, the ubiquitin-proteasome or other proteolytic systems. The ubiquitin-proteasome system is the principal pathway that degrades soluble proteins, whereas the autophagy/lysosomal system is primarily responsible for clearing insoluble protein aggregates. There are three distinct autophagic pathways: Macroautophagy, microautophagy and chaperone-mediated autophagy (CMA).

In macroautophagy, organelles and macromolecular components are first surrounded by a double membrane, designated the autophagosome or autophagic vacuole (AV), which then fuses with lysosomes to form autolysosomes (Figure 3). The protein microtubule-associated protein 1, light chain 3 (LC3) is anchored to the vesicle membrane by conjugation to phosphatidylethanolamine (PE). While the un-conjugated LC3 is called LC3-I, the PE-conjugated LC3 is referred to as LC3-II and is a specific marker for autophagosomes (119). Autophagosomes then undergo several microtubule-(70) and dynein-dependent maturation events (80, 134, 141), including fusions with multivesicular bodies, early and/or late endosomes (11), before eventually fusing with lysosomes (37, 38). In microautophagy, the lysosome invaginates its own membrane, resulting in the uptake of segments of the cytoplasm (151). Finally, in CMA, individual proteins are targeted to lysosomes for degradation (102), CMA is tightly regulated, but can under extreme conditions result in cell death and carcinogenesis (47).

Figure 3.

The autophagy pathway is affected at different steps in the various types of dementias. AD is associated with a decreased expression of Beclin-1 leading to impaired autophagy initiation in addition to inhibited autophagosome degradation. PD and DLB are characterized by an increase in mTor and a decrease in Atg7 expression. These alterations are predicted to result in deficient initiation of the autophagic process, but this has not been experimentally established. Rare forms of FTD are caused by CHMP2B and VCP mutations, which lead to impaired autophagosome maturation. The HIV protein, Nef, may block autophagosome maturation by interacting with Beclin-1 leading to autophagy impairment in HIV-associated dementia. AD, Alzheimer’s disease; PD, Parkinson’s disease; DLB, Dementia with Lewy bodies; FTD, Frontotemporal dementia.

Autophagy is involved in the intracellular degradation of aggregation-prone α-syn (178) and huntingtin (136, 150) (Figure 3). Autophagic vacuoles have been identified in dystrophic neurites in AD brains and may be a site for Aβ production (184, 185). In parallel, elimination of basal neuronal autophagy is sufficient to cause neurodegeneration in the absence of other insults (55, 83). In neurodegenerative disorders such as AD, PD, Huntington’s disease (HD) (8, 128) and HAND, the autophagy pathway is deregulated and might contribute to the progressive accumulation of toxic proteins (Figure 3).

In this context, the main objective of this manuscript will be to review some of the studies in dementia patients and experimental models supporting a role for alterations in autophagy.

Autophagy alterations in Alzheimer’s Disease

Amyloidogenic processing of APP by secretases results in the release of APP C-terminal fragments (APP-CTF) and Aβ. Both contribute to the pathogenesis of AD and can display neurotoxic properties (22, 176). Alterations in autophagy might be implicated in the pathogenesis of AD by failing to clear aggregated Aβ and by playing a role in APP metabolism (Figure 4). Recent studies indicate that the autophagocytic pathology observed in AD most likely arises from impaired clearance of autophagic vacuoles (AVs) rather than strong autophagy induction alone (126–128, 184) suggesting selective alterations in molecular components of the autophagy pathway.

Figure 4.

A possible role for Beclin 1 in AD. In healthy individuals, APP is transcribed in the endoplasmic reticulum (ER, grey), modified in the Golgi network and then shuttled to the cell surface through the secretory pathway. The cell can recycle APP through endocytosis. APP can then either be degraded through the autophagy - lysosome (Lys) system, or APP can be recycled via the recycling endosomes (RE) and enter the cycle again. In AD brains and Beclin 1 deficient cells, induction of autophagy (through the complex with Vps34) and autophagosomal degradation (potentially through a complex with an unknown binding partner) seem to be impaired. As a consequence, APP containing vesicles (endosomes, autophagosomes, and others) build up inside the cell. APP is increasingly cleaved by secretases and APP-CTF and Abeta are being generated and possibly released from the cell. The disruption of autophagosomal degradation includes an increasing accumulation of autophagosomes. This accumulation can serve as sites of Abeta generation, further inhibiting APP turnover and degradation. EE, early endosome; LE, late endosome, AV, Autophagic vesicle.

While it is still not completely clear how dysfunction of the autophagy pathway might contribute to neurodegeneration and AD, recent studies suggest a role for Beclin-1 in AD and mild cognitive impairment (131). Beclin-1 is the human homolog of the yeast autophagy protein Atg6 (73). Beclin-1 is necessary for autophagy (97, 132, 186, 187). It regulates the autophagy-promoting activity of Vps34 (188), and is involved in the recruitment of membranes to form autophagosomes. Beclin-1 also interacts with Bcl-2 (98) and may thus be involved in regulating cell death. Beclin-1 mRNA and protein are expressed in neurons and glia in human and mouse brains (98). Knockout mice lacking Beclin-1 (Bcn1−/−) die during embryogenesis (132, 187). In contrast, Bcn1+/− mice are viable. They have reduced autophagosome formation in skeletal muscle, bronchial epithelial cells and B lymphocytes (132), but the neuronal phenotype of these mice has not been characterized.

Recently, heterozygous deletion of Beclin-1 in mice has been reported to decrease neuronal autophagy and promote neuronal degeneration (131). Moreover, in a mouse model for AD, reduction of Beclin-1 expression results in increased accumulation of APP fragments and Aβ, increased neurodegeneration and increased inflammation (131). In contrast, gene therapy using locally injected lentivirus expressing Beclin-1 reduced amyloid pathology in APP transgenic (tg) mice. Autophagy protects neurons from Aβ induced cytotoxicity (64) and intracellular APP and APP-CTFs can be reduced by autophagy activation, indicating that the Beclin 1-PIK3C3 complex might play a role in Aβ clearance by regulating APP processing (68, 69).

Beclin-1 forms a core complex with the class III PI(3) kinase PIK3C3 (also known as Vps34) (79). Other proteins such as UVRAG, PIK3R4/Vps15, Atg14L, or Rubicon, join this complex depending on its physiological function in autophagy or endosomal trafficking (66, 96, 190). Beclin-1 and PIK3C3 mRNA and protein are expressed in human and mouse brains (67, 94). Thus, there are at least two aspects to autophagy pathology in AD (Figure 4). The first involves accumulation of abundant autophagosomes in dystrophic neurites (126, 128, 184) indicating impaired autophagosomal degradation (126). This has been confirmed in recent studies that detected increased levels of LC3-II in AD brains (28, 68). In the other end, Beclin-1 (131) and PIK3C3 are decreased in AD, suggesting impaired autophagy initiation in addition to inhibited autophagosomal degradation (Figure 3). This suggests a possible dual role of Beclin-1; one in autophagy initiation, in a complex with PIK3C3, and another in autophagosomal degradation, potentially in a complex with other proteins (68, 69, 190) (Figure 3).

Interestingly, while activation of autophagy with rapamycin has been reported to be protective in APP tg models (155), pharmacological inhibition of autophagosomal-lysosomal degradation with Bafilomycin A1 causes a comparable accumulation of APP and APP-metabolites in autophagosomes (53, 146). Although the mechanisms underlying the rapamycin findings are controversial (189), these data provide evidence that the autophagy pathway is altered in AD and modulating this pathway might represent a novel therapeutic approach for AD (Figure 4).

Alterations in autophagy in α-Synucleinopathies

Progressive accumulation of α-syn in selected regions of the CNS has been shown to play an important role in the neurodegenerative process in PD, LBD and other neurological conditions (58), for which the unifying term, synucleinopathies, has been proposed (56). In these disorders, the abnormal accumulation of α-syn is not limited to the striato-nigral system but also affects the limbic areas, the insula, frontal cortex and subcortical nuclei (14, 65, 106, 160). Fibrillar α-syn aggregates form LBs and Lewy neurites; the role of these inclusions is uncertain, however some studies suggest that they might represent a protective mechanism of isolating more toxic α-syn species (57).

Recent studies indicate that rather than the fibrils, α-syn oligomers that form protofibrils (26, 89) and probably pore-like structures (89) might be responsible for the characteristic synaptic damage and neuronal loss observed in LBD. While in familial forms of parkinsonism, mutations in the α-syn molecule (121, 173) and in other components involved in α-syn clearance (35) might promote and accelerate the formation of toxic α-syn intermediates, in sporadic forms of LBD the etiopathogenesis is less clear.

Therefore, impaired clearance of the α-syn aggregates might play an important role in the pathogenesis of PD and DLB (10, 30) (Figure 3). Among the lysosomal pathways involved, the autophagy signaling cascade has emerged as a key mechanism for the removal of α-syn aggregates. In PD recent studies have suggested that α-syn aggregates might interfere with the autophagy mechanisms and lead to neurodegeneration (30, 118, 120, 138, 140, 156). Mutant forms of α-syn found in familial PD patients (30) as well as oxidized forms of α-syn (105) found in sporadic PD and DLB have been shown to block autophagy, and α-syn contains a consensus sequence for CMA targeting (Figure 3). In neuronal cell cultures (181) and in tg mice, α-syn overexpression is associated with impaired autophagy and neurodegeneration that is reversed by Beclin-1 (154). Further supporting a role for lysosomal dysfunction in LBD, previous studies have shown that in lysosomal storage disorders such as Gaucher disease (161, 172) and Niemann-Pick disease (144), there is increased susceptibility to develop parkinsonism and α-syn accumulation.

Taken together, these lines of evidence suggest that in DLB and PD, specific molecular defects in the autophagy pathway might play a role in the pathogenesis of these disorders. In this respect, recent studies have shown that mTor levels were increased and Atg7 levels were reduced in the brains of patients with DLB and α-syn tg mice (Figure 3). Moreover, rapamycin treatment or viral-mediated delivery of Atg7 ameliorated α-syn accumulation and the related neuropathology. This is consistent with previous in vivo studies showing that rapamycin is neuroprotective in models of neurodegeneration (129, 135), AD (12) and HD (136, 145). Moreover, a recent study showed that blocking mTor by overexpression of the translation inhibitor Thor (4E-BP) could reduce the pathologic features in PD models, including degeneration of dopaminergic neurons in Drosophila (159). In addition, rapamycin activates 4E-BP in vivo and is also capable of ameliorating the pathology associated with mutations in other PD-associated genes such as Pink1 and parkin (159).

The mechanisms through which increased mTor and reduced Atg7 might participate in the neuropathology of DLB are not completely clear. Although there are mTor-independent pathways of autophagy induction, these alterations are predicted to result in deficient initiation of the autophagy process. This in turn might result in progressive accumulation of α-syn aggregates that further interfere with the fusion of lysosomes and formation of autophagosomes, as has been suggested by other studies (30, 105, 181). This may lead to the formation of enlarged and atypical AV-like structures (154). Consistent with these studies, recent evidence in cell-based models of PD-like pathology indicate that alterations in lysosomal functioning and autophagy might participate in the mechanisms of α-syn-mediated neurodegeneration (23, 30, 118, 120, 138, 140, 156).

Other animal studies have shown that deletion of Atg7 results in motor deficits and neurodegeneration (83, 84). Moreover, toxin models, such as animals exposed to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), have also revealed autophagic dysfunction associated with alterations in signal transduction pathways (192). In addition, increased susceptibility to PD appears to be associated with polymorphisms in lysosomal genes such as those associated with Gaucher disease and Niemann-Pick disease. Moreover, recent studies have shown that reduced Cathepsin D expression results in α-syn accumulation and degeneration of the dopaminergic system in experimental models and in patients with PD (24). Cathepsin D is now considered one of the main lysosomal enzymes involved in α-syn degradation (149) and overexpression of Cathepsin D reduces the pathology associated with α-syn accumulation (31).

Multiple System Atrophy (MSA) is another neurodegenerative disorder characterized by abnormal accumulation of α-syn, however unlike the neuronal aggregation of α-syn observed in DLB and PD, in MSA α-syn accumulation is observed in oligodendrocytes in inclusions termed Glial Cell Inclusions (GCI). Despite the primarily oligodendrocytic accumulation of α-syn, MSA patients also display considerable neuronal loss in the striatum, cerebellum, brainstem and cortex, accompanied by astrogliosis, microgliosis and myelin loss (174, 183). Interestingly, a recent study has reported p62 immunoreactivity (a ubiquitin-associated autophagy substrate) in GCI’s of a MSA patient (110) highlighting the possibility that autophagocytic alterations may also play a role in this disorder.

In conclusion, these data support the notion that alterations in the autophagy pathway play a role in α-synucleinopathies such as DLB/PD and MSA and support the possibility that modulators of the autophagy pathway may also have potential therapeutic effects in these disorders (Figure 3).

Alterations in autophagy in Frontotemporal Dementia

Frontotemporal dementia is a neurodegenerative disorder characterized by progressive changes in behavior, personality, and language (13). The FTD condition is one of three syndromes caused by frontotemporal lobar degeneration (FTLD), and is the second most common early-onset dementia after Alzheimer’s Disease. Common neuropathological findings in FTD are atrophy and neuronal loss in the frontal and temporal lobes (13).

A high proportion of FTD cases have been reported to have a hereditary component and several pathogenic mutations have been identified to cause FTD. Mutations in tau (tau-positive FTD with parkinsonism, FTDP-17) or progranulin (tau-negative FTLD with ubiquitin-positive inclusions, FTLD-U) represent the most common forms of autosomal dominant inherited FTD (148). It is interesting to note that a number of mutations linked to FTD impact genes associated with later steps of autophagy including the CHMP2B (charged multivesicular body protein 2B) and VCP (valosin containing protein) genes (Figure 3).

Mutations in the CHMP2B gene are a rare cause of autosomal dominant FTD. One of the most widely studied examples of this mutation is FTD linked to chromosome 3 (FTD-3), which was discovered in a large Danish family (15, 51). This disease-causing mutation leads to C-terminal truncations of the CHMP2B protein, a component of ESCRT-III (endosomal sorting complex required for transport III) (Figure 3).

ESCRT-III is essential for formation of multivesicular bodies, which are late endosomal compartments formed through invagination and budding of vesicles into the lumen of endosomes (91). Defective ESCRT function leads to accumulation of cytoplasmic protein aggregates containing ubiquitin, p62 and TAR DNA binding protein 43 (TDP-43) (142). Recent studies using cellular and Drosophila models for HD have shown that reduced ESCRT levels inhibit the clearance of expanded polyglutamine aggregates and aggravate their neurotoxic effect (142).

Overexpression of C-terminally truncated CHMP2B in PC12 and human neuroblastoma cells produces enlarged endosomes, which disrupts normal endosomal trafficking and autophagic clearance of intracellular proteins (152, 171). Moreover, mutant CHMP2B has been shown to cause autophagosome accumulation, dendritic retraction, and subsequent neuronal cell loss in cultured cortical neurons, likely a result of insufficient fusion between autophagosomes and lysosomes (90). Furthermore, inhibition of autophagy delays neuronal cell loss caused by ESCRT-III dysfunction indicating that accumulation of autophagosomes is detrimental to the survival of neurons (92). Recently, it was shown that mutant CHMP2B impairs maturation of dendritic spines in cultured hippocampal neurons (9), a potential mechanism of neurodegeneration in FTD.

Another mutation that has been linked to FTD affects VCP/p97, one of the best characterized type II AAA (ATPases associated with diverse cellular activities) ATPases involved in vesicle fusion, proteasomal activity and autophagy (148) (Figure 3). Mutations in VCP are the cause of inclusion body myopathy associated with Paget’s disease of bone and frontotemporal dementia (IBMPFD) and a causative factor for amyotrophic lateral sclerosis (ALS). IBMPFD is a progressive, fatal genetic disorder with variable penetrance, predominately affecting muscle, bone, and brain (179). TDP-43 and ubiquitin are major components of inclusions characteristic of VCP-associated FTD, placing this disease in the group of neurodegenerative diseases termed TDP-43 proteinopathies (18).

Several studies have implicated VCP in the autophagy pathway. Expression of disease-associated VCP mutants (R155H and A232E) or overexpression of dominant-negative VCP in mouse embryonic fibroblasts cause accumulation of immature autophagic vesicles, indicating that VCP is essential for autophagosome maturation (163) (Figure 3). A Drosophila model of IBMPFD reveals that mutations of the VCP homolog, TER94, lead to redistribution of TDP-43 from the nucleus to the cytoplasm, replicating the pathological hallmark of IBMPFD and other TDP-43 proteinopathies (139). Mice expressing mutant VCP develop pathology similar to humans with IBMPFD including degeneration of muscle, bone and brain. Immunohistochemical analyses of these mice show progressive cytoplasmic accumulation of TDP-43 and ubiquitin-positive inclusion bodies in muscle and brain (7, 32). Moreover, LC3-II staining of brain sections from mice expressing VCP R155H reveals an accumulation of autophagosomes suggesting impaired autophagy in brain pathogenesis (7).

Although CHMP2B and VCP mutations are very rare among FTD patients, their involvement in the autophagy pathways may have important implications for FTD and other neurodegenerative diseases (Figure 3).

Alterations in autophagy in HIV-associated cognitive disorders

In the US, more than 1 million people are living with HIV and the aging population represents one of the fastest growing groups with HIV (1, 2, 147). The CDC estimates that by 2015, half of all Americans living with HIV will be over the age of 50 (1, 2, 153).

In the CNS, microglial cells have been identified as a primary reservoir for HIV-1 infection (41, 46, 52, 180) with productive infection also detected in astrocytes (20). With the advent of HAART, the abundance of active HIV in the brain and overt dementia has declined, however, as the number of treated subjects with chronic HIV infection increases, the prevalence of HAND is rising despite therapeutic intervention (48, 62, 63, 107, 113, 143, 170).

Neurocognitive alterations are among the most common disorders in HIV-infected patients (114), affecting 15–50% of HIV patients (62, 112), and susceptibility of the aging HIV population to cognitive alterations is becoming increasingly evident (114, 167, 168). For example, verbal memory, visual memory and psychomotor speed are more affected in HIV+ aged patients (166). The prevalence of HIV associated cognitive deficits is 7.2% in the >40 yr vs. 27.3% in the >50 yr group (2, 87). Therefore, identification of new targets that might protect the CNS from the toxic effects of HIV might be an important therapy for patients with HAND.

The mechanisms leading to neurodegeneration in HIV encephalitis (HIVE) might involve a variety of pathways including damage to the blood-brain barrier (BBB) (74, 182), excitotoxicity (61, 75), oxidative stress (122, 169), mitochondrial dysfunction (104, 165), calcium dysregulation (60, 111) and signaling alterations (36, 76, 101, 124, 133, 158, 177).

In the aging population with HIV, in addition to these factors other mechanisms might be at play. Among them, defective protein quality control might play a central role. During the aging process and in neurodegenerative disorders, defects on these clearance pathways may lead to progressive accumulation of misfolded proteins and formation of neurotoxic oligomers (28, 29, 128). In patients with HIVE, a number of studies have shown defects in proteasome function (40, 125), proteolysis (137) and autophagy (5, 6, 191) (Figure 3). We have recently shown that in the CNS of aged HIV human cases and in tg mice expressing HIV-gp120 protein (GFAP-gp120 tg) (162), abnormal functioning of neuronal autophagy (17, 21, 28, 184, 185) might result in accumulation of Aβ, α-syn and Tau. Neurodegeneration is also linked to defects in neuronal autophagy in recent studies of patients with HIVE and in the simian immunodeficiency virus encephalitis (SIVE) model (5, 6).

Likewise, recent reports have shown that autophagy in macrophages and neurons might be dysregulated in patients with HIV (5, 6, 191). Here, it is worth noting that while some studies have reported inhibition of neuronal autophagy in HIVE (5, 6, 191), we have reported an increase expression of autophagy markers (28). This apparent difference can be best explained by the possibility that in HIVE, although some markers of autophagy are increased, the overall process is actually blocked, resulting in the accumulation of molecular components of the autophagy pathway and formation of abnormal autophagosomes. Consistent with this observation, recent studies indicate that the HIV protein Nef blocks the maturation of autophagosomes (85) (Figure 3).

The mechanisms by which HIV proteins might interfere with autophagy during aging are unknown. One possibility is that HIV proteins released from infected microglia might interfere with neuronal autophagy by directly interacting with components of the autophagy pathway. Supporting this possibility, previous studies have shown that HIV1 exploits the autophagy pathway for biogenesis, that HIV1 can be eliminated via autophagy. Moreover, the HIV protein Nef acts as an anti-autophagic maturation factor (85) (Figure 3). In HIV-infected macrophages, Nef blocks autophagosome maturation, probably stabilizing an as yet unknown intracellular compartment for HIV biogenesis (85). Nef might interact with Beclin-1 in the UVRAG-Beclin-1-hVps34 complex to inhibit autophagosome maturation (85) by inhibiting lysosomal fusion and thereby affecting the membrane redistribution of hVps34 (Figure 3).

Conclusions

While there are a many different forms of dementia each characterized by a distinctive protein profile, they all share a common theme of abnormal protein aggregation linked to alterations in protein clearance mechanisms, most notably components of the autophagocytic pathway (Figure 3). Further studies into the involvement of autophagy in neurodegeneration may help elucidate common mechanisms underlying protein accumulation in these disorders and may have an impact on potential therapeutic interventions for these diseases.