Post-translational modifications of tau protein in Alzheimer’s disease

Summary. Microtubule-associated protein tau undergoes several post-translational modifications and aggregates into paired helical filaments (PHFs) in Alzheimers disease (AD) and other tauopathies. These modifications of tau include hyperphosphorylation, glycosylation, ubiquitination, glycation, polyamination, nitration, and proteolysis. Hyperphosphorylation and glycosylation are crucial to the molecular pathogenesis of neurofibrillary degeneration of AD. The others appear to represent failed mechanisms for neurons to remove damaged, misfolded, and aggregated proteins. This review summarizes the abnormal post-translational modifications of tau and discusses the pathophysiological relevance of hyperphosphorylation and glycosylation of tau. Total tau and phosphorylated tau levels in cerebrospinal fluid as a diagnostic biomarkers are also reviewed. Analyses of the current advances in tau modifications suggest that intervention addressing these abnormalities may offer promising therapeutic opportunities to prevent and treat neurofibrillary degeneration of AD and other tauopathies.     

AMPK is abnormally activated in tangle- and pre-tangle-bearing neurons in Alzheimer’s disease and other tauopathies

Tauopathies represent a class of neurodegenerative disorders characterized by abnormal tau phosphorylation and aggregation into neuronal paired helical filaments (PHFs) and neurofibrillary tangles. AMP-activated protein kinase (AMPK) is a metabolic sensor expressed in most mammalian cell types. In the brain, AMPK controls neuronal maintenance and is overactivated during metabolic stress. Here, we show that activated AMPK (p-AMPK) is abnormally accumulated in cerebral neurons in 3R+4R and 3R tauopathies, such as Alzheimer’s disease (AD), tangle-predominant dementia, Guam Parkinson dementia complex, Pick’s disease, and frontotemporal dementia with parkinsonism linked to chromosome 17, and to a lesser extent in some neuronal and glial populations in the 4R tauopathies, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease. In AD brains, p-AMPK accumulation decorated neuropil threads and dystrophic neurites surrounding amyloid plaques, and appeared in more than 90% of neurons bearing pre-tangles and tangles. Granular p-AMPK immunoreactivity was also observed in several tauopathies in apparently unaffected neurons devoid of tau inclusion, suggesting that AMPK activation preceded tau accumulation. Less p-AMPK pathology was observed in PSP and CBD, where minimal p-AMPK accumulation was also found in tangle-positive glial cells. p-AMPK was not found in purified PHFs, indicating that p-AMPK did not co-aggregate with tau in tangles. Finally, in vitro assays showed that AMPK can directly phosphorylate tau at Thr-231 and Ser-396/404. Thus, activated AMPK abnormally accumulated in tangle- and pre-tangle-bearing neurons in all major tauopathies. By controlling tau phosphorylation, AMPK might regulate neurodegeneration and therefore could represent a novel common determinant in tauopathies.     

Treatments in Alzheimer’s disease

Journal of Neurology -     

Progress in Alzheimer’s disease

After more than one century from Alois Alzheimer and Gaetano Perusini’s first report, progress has been made in understanding the pathogenic steps of Alzheimer’s disease (AD), as well as in its early diagnosis. This review discusses recent findings leading to the formulation of novel criteria for diagnosis of the disease even in a preclinical phase, by using biological markers. In addition, treatment options will be discussed, with emphasis on new disease-modifying compounds and future trial design suitable to test these drugs in an early phase of the disease.     

Astrocytes in Alzheimer’s disease

The circuitry of the human brain is formed by neuronal networks embedded into astroglial syncytia. The astrocytes perform numerous functions, providing for the overall brain homeostasis, assisting in neurogenesis, determining the micro-architecture of the grey matter, and defending the brain through evolutionary conserved astrogliosis programs.     

The genetics of Alzheimer’s disease

Alzheimer’s disease (AD) is a genetically complex disorder. Mutations in the amyloid precursor protein and presenilin 1 (PS1) genes are fully penetrant and cause early-onset AD. Mutations in presenilin 2, a PS1 homologue, cause partially penetrant autosomal dominant AD with onset age beginning at 40 years and extending past 75 years. A fourth gene, apolipoprotein E (ApoE) is a riskfactor for late-onset AD. Over 40 genes have been tested as AD candidate genes, yet none has been clearly established as an AD risk factor. Linkage studies have implicated a number of chromosome regions as possible sites for late-onset AD loci with the strongest evidence being for chromosome 12. Candidate genes in this regioninclude α2-macroglobulin (A2M) and low-density lipoprotein receptor-related gene (LRP), although neither has been clearly established as an AD gene. Identification of additional late-onset genes will require larger samples, more sophisticated analysis methods, and large-scale positional cloning efforts.     

Glycosylation of microtubule-associated protein tau in Alzheimer’s disease brain

In the neurofibrillary pathology of Alzheimer’s disease (AD), neurofibrillary tangles (NFTs) contain paired helical filaments (PHFs) as their major fibrous component. Abnormally hyperphosphorylated, microtubule-associated protein tau is the major protein subunit of PHFs. A recent in vitro study showed that PHF tangles from AD brains are highly glycosylated, whereas no glycan is detected in normal tau. Deglycosylation of PHF tangles converts them into bundles of straight filaments and restores their accessibility to microtubules. We showed that PHF tangles from AD brain tissue were associated with specific glycan molecules by double immunostaining with peroxidase and alkaline phosphatase labeling. Intracellular tangles and dystrophic neurites in a neuritic plaque with abnormally hyperphosphorylated tau, detected with the monoclonal antibodies AT-8 and anti-tau-2, were also positive with lectin Galanthus nivalis agglutinin (GNA) which recognizes both the N- and O-glycosidically linked saccharides. Colocalization was not seen in the extracellular tangles and amyloid deposition, suggesting that the glycosylation of tau might be associated with the early phase of insoluble NFT formation. Thus, although abnormal phosphorylation might promote aggregation of tau and inhibition of the assembly of microtubules, glycosylation mediated by a GNA-positive glycan appears to be responsible for the formation of the PHF structures in vivo. Received: 25 June 1998 / Revised: 3 November 1998 / Accepted: 20 November 1998     

The concept of FDG-PET endophenotype in Alzheimer’s disease

Often viewed as a potential tool for preclinical diagnosis in early asymptomatic stages of Alzheimer’s disease (AD), the term “endophenotype” has acquired a recent popularity in the field. In this review, we analyze the construct of endophenotype—originally designed to discover genes, and examine the literature on potential endophenotypes for the late-onset form of AD (LOAD). We focus on the [18F]-fluoro-2-deoxyglucose (FDG) PET technique, which shows a characteristic pattern of hypometabolism in AD-related regions in asymptomatic carriers of the ApoE E4 allele and in children of AD mothers. We discuss the pathophysiological significance and the positive predictive accuracy of an FDG-endophenotype for LOAD in asymptomatic subjects, and discuss several applications of this endophenotype in the identification of both promoting and protective factors. Finally, we suggest that the term “endophenotype” should be reserved to the study of risk factors, and not to the preclinical diagnosis of LOAD.     

The significance of neuroinflammation in understanding Alzheimer’s disease

Summary. The interest of scientists in the involvement of inflammation-related mechanisms in the pathogenesis of Alzheimer’s disease (AD) goes back to the work of one of the pioneers of the study of this disease. About hundred years ago Oskar Fischer stated that the crucial step in the plaque formation is the extracellular deposition of a foreign substance that provokes an inflammatory reaction followed by a regenerative response of the surrounding nerve fibers. Eighty years later immunohistochemical studies revealed that amyloid plaques are indeed co-localized with a broad variety of inflammation-related proteins (complement factors, acute-phase proteins, pro-inflammatory cytokines) and clusters of activated microglia. These findings have led to the view that the amyloid plaque is the nidus of a non-immune mediated chronic inflammatory response locally induced by fibrillar Aβ deposits. Recent neuropathological studies show a close relationship between fibrillar Aβ deposits, inflammation and neuroregeneration in relatively early stages of AD pathology preceding late AD stages characterized by extensive tau-related neurofibrillary changes. In the present work we will review the role of inflammation in the early stage of AD pathology and particularly the role of inflammation in Aβ metabolism and deposition. We also discuss the possibilities of inflammation-based therapeutic strategies in AD.     

Cerebrospinal fluid protein biomarkers for Alzheimer’s disease

The introduction of acetylcholine esterase (AChE) inhibitors as a symptomatic treatment of Alzheimer’s disease (AD) has made patients seek medical advice at an earlier stage of the disease. This has highlighted the importance of diagnostic markers for early AD. However, there is no clinical method to determine which of the patients with mild cognitive impairment (MCI) will progress to AD with dementia, and which have a benign form of MCI without progression. In this paper, the performance of cerebrospinal fluid (CSF) protein biomarkers for AD is reviewed. The diagnostic performance of the three biomarkers, total tau, phospho-tau, and the 42 amino acid form of β-amyloid have been evaluated in numerous studies and their ability to identify incipient AD in MCI cases has also been studied. Some candidate AD biomarkers including ubiquitin, neurofilament proteins, growth-associated protein 43 (neuromodulin), and neuronal thread protein (AD7c) show interesting results but have been less extensively studied. It is concluded that CSF biomarkers may have clinical utility in the differentiation between AD and several important differential diagnoses, including normal aging, depression, alcohol dementia, and Parkinson’s disease, and also in the identification of Creutzfeldt-Jakob disease in cases with rapidly progressive dementia. Early diagnosis of AD is not only of importance to be able to initiate symptomatic treatment with AChE inhibitors, but will be the basis for initiation of treatment with drugs aimed at slowing down or arresting the degenerative process, such as γ-secretase inhibitors, if these prove to affect AD pathology and to have a clinical effect.     

Alzheimer’s disease

Psychiatric Quarterly - It would appear, on the basis of this study, that Alzheimer’s disease is a distinct clinicopathologic entity which, while not common, is not so rare as commonly...     

Alzheimer’s disease

Conclusions It would appear, on the basis of this study, that Alzheimer's disease is a distinct clinicopathologic entity which, while not common, is not so rare as commonly believed.Finally, it is pertinent to emphasize that familiarity with the clinical picture will show that many more cases exist than have hitherto been suspected.     

Neuroprotective strategies in Alzheimer’s disease

In addition to strategies designed to decrease amyloid beta (Aβ) levels, it is likely that successful Alzheimer’s disease (AD) therapeutic regimens will require the concomitant application of neuroprotective agents. Elucidation of pathophysiological processes occurring in AD and identification of the molecular targets mediating these processes point to potential high-yield neuroprotective strategies. Candidate neuroprotective agents include those that interact specifically with neuronal targets to inhibit deleterious intraneuronal mechanisms triggered by Aβ and other toxic stimuli. Strategies include creating small molecules that block Aβ interactions with cell surface and intracellular targets, down-regulate stress kinase signaling cascades, block activation of caspases and expression of pro-apoptotic proteins, and inhibit enzymes mediating excessive tau protein phosphorylation. Additional potential neuroprotective compounds include those that counteract loss of cholinergic function, promote the trophic state and plasticity of neurons, inhibit accumulation of reactive oxygen species, and block excitotoxicity. Certain categories of compounds, such as neurotrophins or neurotrophin small molecule mimetics, have the potential to alter neuronal signaling patterns such that several of these target actions might be achieved by a single agent.     

Memory suppression in Alzheimer’s disease

An important challenge for memory is the competition between appropriate and inappropriate information during retrieval. This competition is normally reduced thanks to controlled inhibitory processes that suppress irrelevant memories. In Alzheimer’s disease (AD), compromise of suppression ability may result in strong competition between relevant and irrelevant memories during retrieval. The present review highlights this issue by examining studies using the directed forgetting method in AD. This method in which participants are typically instructed to forget no longer relevant information is argued to reflect suppression in memory. Studies using the directed forgetting method suggest that AD participants experience difficulties when they are asked to suppress no longer relevant information in working, autobiographical, source and destination memory. Difficulties in suppressing irrelevant information, as may be observed in AD, may hamper memory retrieval by activating irrelevant memories at the expense of relevant ones.     

Anti-inflammatory agents in Alzheimer’s disease

Epidemiologic studies have raised expectations that existing anti-inflammatory drugs may be useful in slowing the progression of Alzheimer’s disease (AD). However, the first large-scale studies of anti-inflammatory drug treatment regimens have been negative. These disappointing results, along with new evidence from cell culture and animal model systems, suggest that the inflammatory hypothesis must be refined. Generalizations about inflammation and anti-inflammatory drugs have not been useful in developing treatment strategies for AD. But new studies suggest that specific anti-inflammatory drugs may have beneficial effects mediated by unexpected mechanisms. Continued exploration of the neuroprotective potential of specific antirheumatic therapies, as well as consideration of treatment duration and subject selection, will improve the outlook for successful development of one or more of these drugs in the prevention or treatment of AD.     

ApoE-dependent plasticity in Alzheimer’s disease

The contribution of neuroplasticity to Alzheimer’s disease (AD) is supported by important effects of apoE on both the pathology of AD and the environmental and developmental factors influencing its etiologies. The earlier age of onset of apoE4 AD patients could be caused by defects in apoE-related compensatory repair mechanisms. The role of apoE in stimulating neuronal regeneration like neurite sprouting has received much support, with apoE4 consistently showing defects both in vitro and in vivo and in AD. In addition, growing evidence indicates that the reduced sprouting activity of apoE4 represents a gain-of-negative function; that is, apoE3-stimulated sprouting increases with increasing apoE3 dose, while any neurite sprouting with apoE4 is decreased with increasing apoE4 dose. Clearly, the dose responses for all relevant apoE activities need evaluation, as well as determination of the physiologically relevant doses in the brain. Because apoE4 plays a major role in the risk and onset of AD for ∼50% of AD cases, therapies that target the mechanism of this increased risk would greatly impact AD prevalence. Possible targets include apoE expression levels and regulation, and apoE protein structure or gene replacement. The gain-of-negative function of apoE4 in neurite sprouting, or any apoE4-specific activity, could have important clinical implications for the pharmacogenetic efficacy of therapeutic drugs that impact or target apoE expression or activity. Some therapeutic drugs, including estrogen that can regulate apoE levels, show apoE isotype-dependent efficacy in AD therapy. Other candidate drugs that could modulate apoE expression include antioxidants, anti-inflammatories, and statins. The contribution of apoE4 to drug efficacy may distinguish mechanisms of disease onset from those of progression, since the pleiotropic effects of apoE and its isotypes raise the strong possibility that the isotypes differ in the mechanism by which they contribute to AD etiology.     

Synaptic degeneration in Alzheimer’s disease

Synaptic loss is the major neurobiological substrate of cognitive dysfunction in Alzheimer’s disease (AD). Synaptic failure is an early event in the pathogenesis that is clearly detectable already in patients with mild cognitive impairment (MCI), a prodromal state of AD. It progresses during the course of AD and in most early stages involves mechanisms of compensation before reaching a stage of decompensated function. This dynamic process from an initially reversible functionally responsive stage of down-regulation of synaptic function to stages irreversibly associated with degeneration might be related to a disturbance of structural brain self-organization and involves morphoregulatory molecules such as the amyloid precursor protein. Further, recent evidence suggests a role for diffusible oligomers of amyloid β in synaptic dysfunction. To form synaptic connections and to continuously re-shape them in a process of ongoing structural adaptation, neurons must permanently withdraw from the cell cycle. Previously, we formulated the hypothesis that differentiated neurons after having withdrawn from the cell cycle are able to use molecular mechanisms primarily developed to control proliferation alternatively to control synaptic plasticity. The existence of these alternative effector pathways within neurons might put them at risk of erroneously converting signals derived from plastic synaptic changes into the program of cell cycle activation, which subsequently leads to cell death. The molecular mechanisms involved in cell cycle activation might, thus, link aberrant synaptic changes to cell death.