Alzheimer mechanisms and therapeutic strategies

Abstract

There are still no effective treatments to prevent, halt, or reverse Alzheimer's disease, but research advances over the past three decades could change this gloomy picture. Genetic studies demonstrate that the disease has multiple causes. Interdisciplinary approaches combining biochemistry, molecular and cell biology, and transgenic modeling have revealed some of its molecular mechanisms. Progress in chemistry, radiology, and systems biology is beginning to provide useful biomarkers, and the emergence of personalized medicine is poised to transform pharmaceutical development and clinical trials. However, investigative and drug development efforts should be diversified to fully address the multifactoriality of the disease.

Figure 1. Multifactorial Basis of Alzheimer’s Disease Pathogenesis

(A) Alzheimer’s disease (AD) is likely caused by co-pathogenic interactions among multiple factors, including APP/Aβ, apoE4, tau, α-synuclein, TDP-43, aging, and various co-morbidities. How exactly they conspire to impair neuronal functions and survival remains to be determined. (B) Aggregation and accumulation of Aβ in the brain may result from increased neuronal production of Aβ decreased degradation by Aβ-degrading enzymes, or reduced clearance across the blood-brain barrier. Aβ oligomers impair synaptic functions and related signaling pathways, changing neuronal activities, and trigger the release of neurotoxic mediators from glial cells. Fibrillar amyloid plaques displace and distort neuronal processes. The lipid transport protein apoE4 impairs Aβ clearance and promotes Aβ deposition. When expressed within stressed neurons, apoE4 is cleaved, to a much greater extent than apoE3, into neurotoxic fragments that disrupt the cytoskeleton and impair mitochondrial functions. Tau, which is normally most abundant in axons, becomes mislocalized to the neuronal soma and dendrites and forms inclusions called neurofibrillar tangles (NFTs). α-synuclein can also self-assemble into pathogenic oligomers and form larger aggregates (Lewy bodies). Both tau and α-synuclein can also be released into the extracellular space, where they may spread to other cells. Vascular abnormalities impair the supply of nutrients and removal of metabolic byproducts, cause microinfarcts, and promote the activation of glial cells.

Figure 2. Aβ in AD Pathogenesis and Related Therapeutic Strategies

(A) Pathogenic Aβ assemblies cause tau-dependent aberrant excitatory network activity and synaptic depression, which may lead directly, or indirectly through hippocampal remodeling, to cognitive dysfunction. Identification and blockade of the upstream mechanisms that trigger this cascade are important objectives. (B) Aβ-dependent aberrant network activity may be caused by impairments of inhibitory interneurons resulting from depletion of voltage-gated sodium channel subunits (VGSC), intracellular activities of neurotoxic apoE4 fragments, or elevated metenkephalin (Enk) levels. Additional mechanisms that may cause neuronal overexcitation in AD include impairment of glutamate transporters (e.g., GLT1), resulting in decreased clearance of glutamate (Glu), and increased neuronal or microglial production of factors that promote excitotoxicity, including arachidonic acid (AA) and quinolinic acid (Quin). (C) hAPP mice have depletions of the VGSC subunit Nav1.1 that impair the function of parvalbumin (PV)-positive inhibitory interneurons (PV cells), resulting in reduced intensity of gamma oscillations and network hypersynchrony. These network abnormalities can be prevented by increasing Nav1.1 levels in PV cells (1) and counteracted, at least temporarily, by behavioral interventions that enhance gamma activity (2). (D) Aβ may impair neuronal functions by receptor-mediated and receptor-independent mechanisms. Potential therapeutic strategies include (1) lowering Aβ production with secretase inhibitors or modulators and enhancing Aβ clearance with antibodies or activation of Aβ-degrading enzymes, (2) blocking the interaction of Aβ with cell surface receptors, and (3) modulating downstream pathways to make the brain more resistant against whatever Aβ cannot be removed effectively and safely.

Figure 3. ApoE4 in AD Pathogenesis and Related Therapeutic Strategies

(A) ApoE4 probably has both Aβ-dependent and Aβ-independent roles in AD pathogenesis. ApoE4 impairs Aβ clearance and promotes Aβ deposition (left). In addition, neuronal apoE4 undergoes proteolytic cleavage to generate neurotoxic fragments, contributing to AD pathogenesis independently of Aβ stresses or injuries, neuronal apoE expression is triggered to facilitate neuronal repair. However, neuronal apoE undergoes proteolytic cleavage, with apoE4 being more susceptible to the cleavage than apoE3, resulting in the formation of neurotoxic fragments. The apoE4 fragments enter the cytosol and cause tau pathology and mitochondrial impairment. Hilar GABAergic interneurons in the dentate gyrus are particularly vulnerable to apoE4 fragment toxicity and the resulting impairments contribute to learning and memory deficits. (C) Neuronal expression of apoE and apoE proteolysis-related neurotoxicity represent targets for the development of novel therapeutics. Inhibiting apoE4 expression in neurons should reduce the level of toxic apoE4 fragments and their downstream detrimental effects. Identification of the protease that cleaves apoE in neurons should enable the development of specific protease inhibitors to reduce the production of neurotoxic apoE fragments. It may also be possible to develop drugs to protect mitochondria and the cytoskeleton from attack by the toxic apoE fragments.

Figure 4. Roles of tau in different tauopathies

Mutations in MAPT, the gene that encodes tau, result in the production of mutant tau and cause certain forms of frontotemporal dementia (FTD) but never AD. In AD, Aβ and apoE4 act upstream of wildtype tau and their adverse effects depend, at least partly, on tau whose structure or function may have been altered by abnormal posttranslational modification, mislocalization or other variables. Indeed, tau reduction prevents Aβ and apoE4 fragments from causing neuronal and behavioral deficits in mouse models. The exact mechanisms by which tau contributes to neuronal dysfunction and degeneration in AD, FTD and other tauopathies remain to be determined.

Figure 5. Impact of Patient Heterogeneity and Modifier Genes on Drug Trials

Hypothetical data clouds with dots representing memory measures obtained in individual human subjects. (A) Without better preselection of patients, potentially effective new drugs may show no efficacy in clinical trials because of the heterogeneity of the patient population tested. (B, C) Stratification of patient populations based on measurements of biomarkers and identification of specific genes could help match up subpopulations with the most suitable drug and significantly increase the chances of identifying better treatments for AD and related disorders.