Amyloidogenic processing of the amyloid precursor protein (APP) by ␤-and ␥-secretases generates several biologically active products, including amyloid-␤ (A␤) and the APP intracellular domain (AICD). AICD regulates transcription of several neuronal genes, especially the A␤-degrading enzyme, neprilysin (NEP). APP exists in several alternatively spliced isoforms, APP 695 , APP 751 , and APP 770 . We have examined whether each isoform can contribute to AICD generation and hence up-regulation of NEP expression. Using SH-SY5Y neuronal cells stably expressing each of the APP isoforms, we observed that only APP 695 up-regulated nuclear AICD levels (9-fold) and NEP expression (6-fold). A characteristic feature of Alzheimer disease (AD) 5 is the presence in the brain of extracellular amyloid plaques composed of the amyloid ␤-peptide (principally A␤ 1-40 and A␤ 1-42 ), which is derived from the transmembrane amyloid precursor protein (APP). Hence, for almost two decades, the amyloid cascade hypothesis (1, 2) has driven much AD research with a focus on the prevention of A␤ accumulation or the enhancement of its clearance as primary therapeutic strategies. In the amyloidogenic pathway of APP metabolism, A␤ is formed through the sequential actions of ␤-and ␥-secretases, whereas the non-amyloidogenic ␣-secretase pathway precludes A␤ formation. Enzymic clearance of A␤ is mediated by several enzymes, of which the metallopeptidase neprilysin (NEP) is a key contributor, and up-regulation of A␤-degrading enzymes is a potential therapeutic strategy (3, 4).Three major isoforms of APP are produced due to the alternative splicing of exons 7 and 8, which encode a 56-amino acid Kunitz-type proteinase inhibitor (KPI) domain and a 19-amino acid domain that shares sequence identity with the OX-2 antigen of thymus-derived lymphoid cells, respectively (5). The longest isoform, APP 770 , contains both the KPI and the OX-2 domains, whereas APP 751 contains only the KPI domain. The shortest isoform, APP 695 , lacks both domains. In the brain, APP 695 is expressed at high levels, and the APP 751/770 isoforms are expressed at significantly lower levels, although there are regional differences, and it has been suggested that the balance between the KPI-and non-KPI-containing isoforms may be an important factor influencing A␤ deposition (6). In the AD brain (7-9) and in response to N-methyl-Daspartate (NMDA) receptor stimulation (10, 11), there is an increase in the proportion of KPI-to non-KPI-containing isoforms of APP. This has led to the suggestion that the KPIcontaining isoforms of APP can exert important neuroprotective functions, and thus their up-regulation in the AD brain or in response to excitotoxic insult may be to protect against further neuronal loss (12, 13).A major unmet scientific need in the AD field is still to understand the normal function of APP (14). An added complexity is whether the different APP isoforms have similar or distinct localizations, metabolism, and roles (15). A long standing enigma in APP biology has additi...

With predictions showing that 131.5 million people worldwide will be living with dementia by 2050, an understanding of the molecular mechanisms underpinning disease is crucial in the hunt for novel therapeutics and for biomarkers to detect disease early and/or monitor disease progression. The metabolism of the microtubule-associated protein tau is altered in different dementias, the so-called tauopathies. Tau detaches from microtubules, aggregates into oligomers and neurofibrillary tangles, which can be secreted from neurons, and spreads through the brain during disease progression. Post-translational modifications exacerbate the production of both oligomeric and soluble forms of tau, with proteolysis by a range of different proteases being a crucial driver. However, the impact of tau proteolysis on disease progression has been overlooked until recently. Studies have highlighted that proteolytic fragments of tau can drive neurodegeneration in a fragment-dependent manner as a result of aggregation and/or transcellular propagation. Proteolytic fragments of tau have been found in the cerebrospinal fluid and plasma of patients with different tauopathies, providing an opportunity to develop these fragments as novel disease progression biomarkers. A range of therapeutic strategies have been proposed to halt the toxicity associated with proteolysis, including reducing protease expression and/or activity, selectively inhibiting protease-substrate interactions, and blocking the action of the resulting fragments. This review highlights the importance of tau proteolysis in the pathogenesis of tauopathies, identifies putative sites during tau fragment-mediated neurodegeneration that could be targeted therapeutically, and discusses the potential use of proteolytic fragments of tau as biomarkers for different tauopathies.

Proteolysis of the amyloid precursor protein (APP) liberates various fragments including the proposed initiator of Alzheimer disease-associated dysfunctions, amyloid-␤. However, recent evidence suggests that the accepted view of APP proteolysis by the canonical ␣-, ␤-, and ␥-secretases is simplistic, with the discovery of a number of novel APP secretases (including ␦-and -secretases, alternative ␤-secretases) and additional metabolites, some of which may also cause synaptic dysfunction. Furthermore, various proteins have been identified that interact with APP and modulate its cleavage by the secretases. Here, we give an overview of the increasingly complex picture of APP proteolysis.Currently over 46 million people worldwide are living with dementia (see the Alzheimer's Disease International website) with Alzheimer disease (AD) 3 representing the most common form of dementia. In AD, the amyloid cascade hypothesis posits that amyloid-␤ (A␤), produced through the sequential proteolytic cleavage of the amyloid precursor protein (APP) by the ␤-and ␥-secretases, is a key molecule in initiating and propagating disease pathology including neurofibrillary tangle formation, neuronal cell loss, aberrant synaptic activity, and brain atrophy that lead to the clinically recognized symptoms of dementia (1). However, identification of the A␤ peptide 25 years ago has not yet led to the advent of a viable therapeutic strategy that can slow or halt the progression of AD. Recent studies have revealed new complexities in the proteolytic processing of APP, including the identification of novel secretases which generate APP metabolites that accumulate in the brains of AD patients and may contribute to the synaptic dysfunction observed in the disease. In addition, numerous proteins are being identified that interact with APP, modulating its proteolysis and A␤ production. These new APP secretases and metabolites, along with the APP interactors, may present novel therapeutic targets that are independent of direct modulation of the canonical secretases and that will need to be considered when evaluating the results from current A␤-directed therapies. In this Minireview, we summarize the recent developments in APP proteolysis focusing on the novel secretases, APP interactors, and APP metabolites that are impacting on our understanding of both APP biology and the neurodegenerative disease process. The Canonical ␣-, ␤-, and ␥-Secretases and APP FragmentsThe generally accepted model of APP proteolysis is that APP is processed by one of two distinct proteolytic pathways (Fig. 1A). In the amyloidogenic pathway, ␤-secretase, the ␤-site APP-cleaving enzyme 1 (BACE1), cleaves APP within the ectodomain and liberates a soluble proteolytic fragment, termed soluble APP␤ (sAPP␤), primarily in the endosomal system from the transmembrane APP holoprotein (2). The remaining C-terminal membrane-bound APP fragment, CTF␤, is subsequently cleaved by the presenilin (PS)-containing ␥-secretase multisubunit complex to liberate the A␤ peptide and the APP intrace...

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