Christina A. Wilson

GSK-3α regulates production of Alzheimer's disease amyloid-β peptides

Alzheimers disease is associated with increased production and aggregation of amyloid-β (Aβ) peptides. Aβ peptides are derived from the amyloid precursor protein (APP) by sequential proteolysis, catalysed by the aspartyl protease BACE, followed by presenilin-dependent γ-secretase cleavage. Presenilin interacts with nicastrin, APH-1 and PEN-2 (ref. 6), all of which are required for γ-secretase function. Presenilins also interact with α-catenin, β-catenin and glycogen synthase kinase-3β (GSK-3β), but a functional role for these proteins in γ-secretase activity has not been established. Here we show that therapeutic concentrations of lithium, a GSK-3 inhibitor, block the production of Aβ peptides by interfering with APP cleavage at the γ-secretase step, but do not inhibit Notch processing. Importantly, lithium also blocks the accumulation of Aβ peptides in the brains of mice that overproduce APP. The target of lithium in this setting is GSK-3α, which is required for maximal processing of APP. Since GSK-3 also phosphorylates tau protein, the principal component of neurofibrillary tangles, inhibition of GSK-3α offers a new approach to reduce the formation of both amyloid plaques and neurofibrillary tangles, two pathological hallmarks of Alzheimers disease.

Investigations of Caspr2, an autoantigen of encephalitis and neuromyotonia

To report clinical and immunological investigations of contactin‐associated protein‐like 2 (Caspr2), an autoantigen of encephalitis and peripheral nerve hyperexcitability (PNH) previously attributed to voltage‐gated potassium channels (VGKC).

Intracellular APP Processing and Aβ Production in Alzheimer Disease

Senile plaques composed of A beta peptides are a histopathological hallmark of Alzheimer disease (AD). A role for A beta in the etiology of AD has been argued from analysis of mutations associated with a subset of early-onset familial AD (FAD). Expression of autosomal dominant mutations in the genes for the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) in affected patients, cultured cells, or transgenic mice leads to increased production of total A beta or increased production of A beta ending at residue 42 (A beta42). Since A beta42 is the more amyloidogenic and toxic species in vitro and is the major component of amyloid senile plaques in vivo, overproduction of this peptide may play a crucial role in the pathogenesis of AD. Thus, an understanding of the production of A beta within the cell in normal and pathological conditions is critical to understanding early events in AD. Studies in cell culture have established that processing of APP to form A beta can occur at multiple locations within the cell and leads to the production of 2 pools of A beta: a secreted pool composed predominantly of A beta40 and a nonsecreted, intracellular pool composed preferentially of more amyloidogenic A beta42. The purpose of this review is to provide a summary of our current understanding of APP processing in the generation of the secreted and intracellular pools of A beta and to propose a model linking the intracellular pool to the formation of extracellular plaques and neuronal pathology in AD.

Presenilins are not required for A beta 42 production in the early secretory pathway.

Presenilins 1 and 2 (PS1/PS2) have been suggested to be γ-secretases responsible for the proteolytic cleavage of amyloid precursor protein (APP) to form amyloid-β (Aβ), a protein implicated in the development of Alzheimers disease. Here we examined whether these presenilins are required for the generation of multiple Aβ species by analyzing the production of several forms of secreted and intracellular Aβ in mouse cells lacking PS1, PS2 or both proteins. Although most Aβ species were abolished in PS1/PS2−/− cells, the production of intracellular Aβ42 generated in the endoplasmic reticulum/intermediate compartment was unaffected by the absence of these proteins, either singly or in combination. These results indicate that production of this pool of Aβ occurs independently of PS1/PS2, and therefore, another γ-secretase activity must be responsible for cleavage of APP within the early secretory compartments.

Degradative organelles containing mislocalized α- and β-synuclein proliferate in presenilin-1 null neurons

Presenilin-1 null mutation (PS1 −/−) in mice is associated with morphological alterations and defects in cleavage of transmembrane proteins. Here, we demonstrate that PS1 deficiency also leads to the formation of degradative vacuoles and to the aberrant translocation of presynaptic α- and β-synuclein proteins to these organelles in the perikarya of primary neurons, concomitant with significant increases in the levels of both synucleins. Stimulation of autophagy in control neurons produced a similar mislocalization of synucleins as genetic ablation of PS1. These effects were not the result of the loss of PS1 γ-secretase activity; however, dysregulation of calcium channels in PS1 −/− cells may be involved. Finally, colocalization of α-synuclein and degradative organelles was observed in brains from patients with the Lewy body variant of AD. Thus, aberrant accumulation of α- and β-synuclein in degradative organelles are novel features of PS1 −/− neurons, and similar events may promote the formation of α-synuclein inclusions associated with neurodegenerative diseases.

Distinct presenilin‐dependent and presenilin‐independent γ‐secretases are responsible for total cellular Aβ production

γ‐Secretase is the second of two proteolytic enzymes involved in the liberation of the β‐amyloid peptide (Aβ) from the amyloid precursor protein (APP). γ‐Secretase cleavage occurs at several intracellular sites, including the Golgi network and the endoplasmic reticulum/intermediate compartment (ER/IC) to produce multiple forms of the Aβ peptide that can be either secreted from the cell or remain intracellular. To date, most evidence has suggested that members of the presenilin protein family are required for γ‐secretase activity. Although it seems that presenilins are indeed necessary for the production of most secreted and intracellular Aβ particularly that generated in downstream organelles, it was shown recently that a presenilin‐independent γ‐secretase is active in the ER/IC and is responsible for the production of a portion of intracellular Aβ42. We discuss the implications of this finding for the understanding of presenilin biology and speculate on the putative identity of the presenilin‐independent cleavage activity.

Convergent Validity and Interrater Reliability of Estimating the ABCD2 Score From Medical Records

Background and Purpose— The ABCD2 score is increasingly used for risk stratification of transient ischemic attack patients. We sought to determine the reliability and convergent validity of retrospective ABCD2 score estimation from medical records. Methods— We compared ABCD2 scores that were prospectively determined by a vascular neurology attending to scores determined retrospectively from medical record review. Emergency department records and neurology consult notes for patients with acute transient ischemic attack were abstracted with explicit ABCD2 scoring redacted. Scores were estimated by 2 independent raters using these records. Estimated ABCD2 component scores, total scores, and risk category were compared both between retrospective raters and with prospectively obtained scores. Reliability was assessed using unweighted &kgr; statistics. Results— Interrater reliability was substantial with 72% exact agreement in total score between retrospective raters (&kgr;=0.64) and nearly perfect with 82% agreement for ABCD2 category (&kgr;=0.71). Interrater agreement was best for age and diabetes mellitus and poorest for clinical features and duration. Agreement between the retrospective raters and prospectively obtained score was >90% for age, blood pressure, and diabetes mellitus, but only ≈70% for clinical features and duration. Retrospectively, estimated total ABCD2 score exactly matched the prospective score in 58% of patients for rater 1 and 44% of patients for rater 2. Retrospectively, estimated ABCD2 category matched the prospectively scored category in 67% of patients for rater 1 and 71% of patients for rater 2. Conclusions— The ABCD2 score can be abstracted from medical records with substantial interrater reliability but limited convergent validity. This may lead to misclassification of risk category in more than one third of patients.

Phiel et al . reply

Replying to T. Jaworski et al. 480, doi:10.1038/nature10615 (2011)GSK-3 has been implicated in the pathogenesis of Alzheimer’s disease through regulation of tau phosphorylation, cellular responses to amyloid-β and processing of amyloid precursor protein (APP) to amyloid-β. We previously reported that inhibition of GSK-3 reduces the accumulation of Aβ40 and Aβ42 (amyloid-ß peptides of 40 and 42 amino acids) in mouse brain and cell culture and that knockdown of Gsk3a reduces amyloid-β accumulation in CHO cells, indicating that Gsk3a contributes to the processing of APP in this context. At about the same time, others reported that knockdown of Gsk3b reduces amyloid-β production and overexpression of active Gsk3b enhances amyloid-β production. A reasonable explanation for these findings, as suggested previously, was that both of these highly similar enzymes contribute to APP processing and their respective contributions depend on cell type, relative abundance and assay conditions. Jaworski et al. now show that APP can be processed in mouse brain in the absence of either Gsk3a or neuronal Gsk3b.

Tau and α-Synuclein in Neurodegenerative Diseases

The past 2 yr have been extremely prolific in the area of neurodegenerative research, particularly with regard to diseases involving the proteins tau and synuclein. Tau aggregation in the form of filaments has long been implicated in diseases such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), as well as others. The recent discovery of tau gene mutations in patients afflicted by a heterogeneous disease entity termed fronto-temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has provided genetic corroboration for the importance of tau in disease and opens novel avenues of investigation into the nature of tau dysfunctions that lead to the demise of neurons. The discovery of mutations in α-synuclein in familial cases of Parkinson’s disease (PD) has led to the revelation that this protein likely plays a prominent role in the etiology of several sporadic neurodegenerative disorders including PD, dementia with Lewy body (DLB) and multiple system atrophy (MSA), collectively grouped as synucleinopathies. In common with the subset of neurodegenerative diseases known as tauopathies because they are characterized by prominent filamentous tau aggregates in neurons and glia, similar fibrillary inclusions also accumulate in the brains of patients with synucleinopathies, but these inclusions are comprised predominantly of α-synuclein aggregates. In this chapter, the current knowledge of synuclein and tau proteins and their possible aberrant, malevolent role(s) in the onset and/or progression of brain diseases is reviewed.