Alzheimer’s disease is one of the most common neurodegenerative diseases worldwide. Clinically, it is characterized by the presence of extracellular amyloid plaques and intracellular neurofibrillary tangles, resulting in neuronal dysfunction and cell death. Central to this disease is the differential processing of the amyloid precursor protein (APP). APP is an integral membrane protein that undergoes proteolytic processing. APP is initially cleaved by α-secretase to generate sAPPα and a C83 carboxy-terminal fragment. The presence of sAPPα is associated with normal synaptic signaling and regulates processes like neuronal survival and synaptic plasticity that contribute to higher order brain functions like learning and memory, and other behaviors. Alternatively, APP may be cleaved sequentially by β-secretase and γ-secretase to release extracellular monomers of varying sizes, the most significant of which is Aβ40/42. In the disease state, an imbalance among APP processing pathways leads to increased aggregation of neurotoxic monomers, yielding Aβ oligomerization and plaque formation. Pathogenic Aβ aggregation results in blocked ion channels, disruption of calcium homeostasis, mitochondrial oxidative stress, impaired energy metabolism and abnormal glucose regulation, altered synaptic function, and ultimately, neuronal cell death. A number of glial cell types, including astrocytes and microglia, have been implicated as both neuroprotective and pathogenic in the context of amyloid monomer, oligomer, and plaque accumulation. Alzheimer’s disease is also characterized by the presence of neurofibrillary tangles, which are composed of hyperphosphorylated forms of the microtubule-associated protein Tau. GSK-3α/β and CDK5 are the kinases primarily responsible for phosphorylation of Tau, although other kinases such as PKC, PKA, and Erk2 are also involved. Hyperphosphorylation of Tau results in the dissociation of Tau from the microtubule, followed by microtubule destabilization and oligomerization of Tau protein, ultimately leading to neurofibrillary tangles within the cell. Progressive accumulation of these tangles leads to apoptosis of the neuron.
Tau, a microtubule-associated protein (MAP), is well known within the context of Alzheimer’s disease (AD) as a main component of intraneuronal neurofibrillary tangles, which are a hallmark of AD and many other neurodegenerative diseases known as tauopathies. In the central nervous system (CNS), tau is a main MAP that normally binds to axonal microtubules to stabilize their quaternary structure during the dynamic process of microtubule assembly. Tau-mediated stabilization enables routine cargo transport along the microtubule highway that - in the context of long axonal projections - is critical for neuronal health and function. This stabilizing function is highly dependent on the generally flexible tertiary structure of tau, which is maintained through phosphorylation of specific sites throughout the protein in both the projection and microtubule binding domains. In the context of AD, tau kinase/phosphatase activity shifts, generating an altered and increased phosphorylation pattern throughout the protein that modifies its tertiary structure. As a result, tau’s capacity for microtubule stabilization is impaired, leading to increased microtubule catastrophe and faulty cargo trafficking. Importantly, pathological hyperphosphorylation of tau increases its susceptibility to aggregate into paired helical filaments, which form into large intracellular neurofibrillary tangles (NFTs), a noted hallmark of AD that is visible in diseased tissue. Microtubule destabilization and NFTs both contribute to the neurotoxicity and neurodegeneration associated with AD and tauopathies.
The amyloid precursor protein (APP) 695 isoform is a type I transmembrane protein that is neuronally expressed and contains amyloidogenic Aβ monomer fragments that are genetically and biochemically implicated in Alzheimer’s disease (AD). Such Aβ monomers result from one of two possible post-translational proteolytic cleavage routes, the determination of which is dependent on many factors including neuronal activity as well as the localization of APP and respective proteolytic secretases. The critical choice point occurs with initial cleavage of APP; proteolysis by α-secretases, such as ADAM10, that reside in the cell membrane generate extracellular soluble APPα (sAPPα) and prevent Aβ formation, as α-secretase cleavage occurs within the Aβ domain. However, alternative cleavage by β-secretases such as BACE1, often occurring in endosomes, preserves the Aβ domain and subsequent cleavage by γ-secretase yields amyloidogenic Aβ monomers. Mutations in γ-secretase complex proteins presenilin 1 and 2 are causative of early-onset AD, presumably due to enhanced generation of Aβ monomers. In the normal state, the α-secretase cleavage pathway is favored, producing the sAPPα and AICD fragments, which play critical roles in healthy neuronal development, maintenance, and function. Yet a predominance towards β-secretase cleavage both attenuates the amount of beneficial sAPPα and increases the production of prion-like Aβ monomers, which can accumulate intracellularly or be trafficked to the cell surface for extracellular release. These monomers self-aggregate into oligomer-built fibrils that accumulate to form extracellular Aβ plaques. These plaques, which are hallmarks of both familial and spontaneous AD, trigger neuroinflammatory pathways and are associated with neurodegeneration and cognitive decline.
Astrocytes, a subset of glial cells named for their star-shaped appearance, are the most abundant cell type in the central nervous system (CNS). Astrocytes play a highly neuroprotective role in the brain by providing neuronal maintenance and support, notably at the blood-brain barrier. Astrocytes also participate in synaptic transmission and neuroinflammatory responses, and serve as the brain’s main source of the apolipoprotein ApoE and cholesterol, which, exported via the ABCA1 transporter, is critical to membrane integrity. Normally, astrocytes aid in Aβ clearance through ApoE production, which positively facilitates Aβ clearance by excretion across the blood brain barrier, or astrocytic uptake through either phagocytosis or receptor-mediated endocytosis, where LRP1 has been well studied. Aβ bound to ApoE and high-density lipoproteins can also be cleared through microglial uptake or microglial-mediated neuroinflammatory responses. Mutations to the APOE gene are critically associated with late-onset Alzheimer’s disease; in this context, it is thought that altered ApoE function leads to extracellular Aβ aggregation and compromised integrity of neuronal membranes, which in turn prompts a neuroinflammatory response that further dysregulates the system. Despite its well-established association with the majority of non-familial AD cases, the mechanistic underpinnings of the pathogenic role of ApoE remain unclear.
A glial cell subtype, microglia are the main arbiters of the neuroimmune system in the central nervous system (CNS). With structurally dynamic processes, microglia constantly scan their environment, acting both as housekeepers involved in neuronal maintenance and synaptic pruning and as defenders against acute and chronic insult. In the context of Alzheimer’s disease (AD), microglia have been observed to surround amyloid plaques and initiate clearance via phagocytosis while spatially restricting plaque proliferation. In particular, mutations of the microglial triggering receptor expressed on myeloid cells 2 (TREM2) are associated with significantly increased risk of late-onset AD. TREM2 is a cell surface immunoreceptor whose activation by a number of polyanionic ligands, including ApoE and Aβ, initiates intracellular signaling cascades through its adaptor protein DAP12. Normally, TREM2 activation promotes chemotaxis, phagocytosis, proliferation, and maintenance activities of microglia that are essential to their neuroprotective function. More specifically, normal TREM2 ligand binding will lead to PI3K and downstream mTOR activation, which inhibits microglial autophagy, a process that is critical to keeping microglia active and in a high metabolic state as they surround Aβ plaques. This role is likely impaired in the absence of TREM2 as Trem2-/- microglia show increased levels of autophagic vesicles. In AD phenotypes, initial impaired microglial clearance of Aβ generates extracellular buildup of aggregates, which trigger a chronic microglial inflammatory response, yielding neurotoxic effects that contribute to AD-associated neurodegeneration.
We would like to thank Prof. Christopher Phiel, University of Colorado-Denver, and Prof. Jeff Kuret, The Ohio State University, Columbus, OH for contributing to this diagram.
created July 2009
revised June 2022
created June 2022
created June 2022
created June 2022
created June 2022