Documents

Alzheimer (1).pdf

Categories
Published
of 8
All materials on our website are shared by users. If you have any questions about copyright issues, please report us to resolve them. We are always happy to assist you.
Related Documents
Share
Description
Indian J Psychiatry 51(1), Jan-Mar 2009 55 CME Neurobiology of Alzheimer’s disease E. Mohandas, V. Rajmohan, B. Raghunath 1 Department of Psychiatry and 1 Neurology, Elite Mission Hospital, Thrissur, Kerala, India How to cite this article: Mohandas E, Rajmohan V, Raghunath B. Neurobiology of Alzheimer’s disease. Indian J Psychiatry 2009;51:55-61. Correspondence: Dr. E. Mohandas, Department of Psychiatry, Elite Mission Hospital, Thrissur, Kerala, India. E-mail: emohandas53@gmail.c
Transcript
  Indian J Psychiatry 51(1), Jan-Mar 2009 55 CME Neurobiology of Alzheimer’s disease E. Mohandas, V. Rajmohan, B. Raghunath 1 Department of Psychiatry and 1  Neurology, Elite Mission Hospital, Thrissur, Kerala, India How to cite this article: Mohandas E, Rajmohan V, Raghunath B. Neurobiology of Alzheimer’s disease. Indian J Psychiatry 2009;51:55-61. Correspondence: Dr. E. Mohandas, Department of Psychiatry, Elite Mission Hospital, Thrissur, Kerala, India. E-mail: emohandas53@gmail.com Alzheimer’s disease (AD) is a devastating neurodegenerative disease, the most common among the dementing illnesses. The neuropathological hallmarks of AD include extracellular β-amyloid (amyloid precursor protein (APP) deposits, intracellular neurobrillary tangles (NFT)), dystrophic neuritis and amyloid angiopathy. The mismetabolism of APP and the defective clearance of β amyloid generate a cascade of events including hyperphosphorylated tau (τ) mediated  breakdown of microtubular assembly and resultant synaptic failure which results in AD. The exact aetiopathogenesis of AD is still obscure. The preeminent hypotheses of AD include amyloid cascade hypothesis and tau hyperphosphorylation. The amyloid hypothesis states that extracellular amyloid plaques formed by aggregates of Aβ peptide generated by the  proteolytic cleavages of APP are central to AD pathology. Intracellular assembly states of the oligomeric and protobrillar species may facilitate tau hyperphosphorylation, disruption of proteasome and mitochondria function, dysregulation of calcium homeostasis, synaptic failure, and cognitive dysfunction. The tau hypothesis states that excessive or abnormal  phosphorylation of tau results in the transformation of normal adult tau into PHF-tau (paired helical lament) and NFTs. Vascular hypothesis is also proposed for AD and it concludes that advancing age and the presence of vascular risk factors create a Critically Attained Threshold of Cerebral Hypoperfusion (CATCH) which leads to cellular and subcellular  pathology involving protein synthesis, development of plaques, inammatory response, and synaptic damage leading to the manifestations of AD. Multiple other aetiological and pathogenetic hypotheses have been put forward including genetics, oxidative stress, dysfunctional calcium homeostasis, hormonal, inammatory-immunologic, and cell cycle dysregulation with the resultant neurotransmitter dysfunctions and cognitive decline. The available therapeutic agents target only the neurotransmitter dysfunction in AD and agents specically targeting the pathogenetic mechanisms like amyloid deposition and tau hyperphosphorylation might provide a denite therapeutic edge. Key words:  Alzheimer’s disease, amyloid cascade, tau hyperphosphorylation, vascular hypothesis, cholinergic defcit ABSTRACT INTRODUCTION  Alzheimer’s disease (AD) is devastating neurodegenerative disease, the most common among the dementing illnesses. The neuropathological hallmarks of AD include extracellular β -amyloid (amyloid precursor protein (APP) deposits, intracellular neurofibrillary tangles (NFT)), dystrophic neuritis, and amyloid angiopathy. The mismetabolism of  APP of unknown etiology (genetic factors contribute only a minority of familial AD) and the defective clearance of β  amyloid generate a cascade of events including hyperphosphorylated tau ( β ) mediated breakdown of microtubular assembly. This results in synaptic failure. Initial glutamatergic deficit at the transentorhinal region paves the way for degenerative changes in the hippocampus and amygdala. In latter stages, the neuronal destruction is manifest in parietal and frontal cortices. Multiple aetiological and pathogenetic hypotheses have been put forward including genetics, oxidative stress, dysfunctional calcium homeostasis, hormonal, inflammatory-immunologic, vascular, and cell cycle dysregulation with the resultant neurotransmitter dysfunctions and cognitive decline. However, amyloid cascade hypothesis along with the tau hyperphosphorylation is still the most proposed pathogenetic mechanism. [1] AMYLOID CASCADE HYPOTHESIS The amyloid hypothesis states that amyloid plaques formed  Indian J Psychiatry 51(1), Jan-Mar 2009 56 by aggregates of A  β  peptide generated by the proteolytic cleavages of APP are central to AD pathology. [1]  APP belongs to a large family of type I membrane proteins with a large extracellular domain and a short cytoplasmic region derived by differential splicing of a single gene transript located on the long arm of chromosome 21. The predominant isoforms, APP770, APP751, and APP695 are expressed  with some tissue specificity. The two longer isoforms of  APP, APP751 and APP770, contain a 56 amino acid long ectodomain. APP is cleaved throughout the Golgi complex by O-glycosylation. The major processing pathway of APP is nonamyloidogenic, the cleavage necessitated by ά -secretase occurring between Lys16 and Leu17 within the A  β  domain preventing the formation of A  β peptides. During this cleavage a soluble ectodomain of APP (sAPP ά ) is released and a 10-kDa C-terminal fragment (p3CT) remains within the membrane. [2,3]  The soluble peptide derived from APP, sAPP ά  may have neuroprotective roles. At least 30% of APP is processed by this pathway. [4,5]  A  β  generation from APP occurs via a two-step proteolytic process involving β - and γ -secretases. The β -site APP cleaving enzyme (BACE1), first cleaves APP to generate a membrane bound soluble C-terminal fragment. A subsequent cleavage of the C-terminal fragment by the γ -secretase activity further generates A  β 40  and A  β 42 . [2]  Both types of peptide could be found in amyloid plaques, but A  β 42  is apparently more directly neurotoxic and has a greater propensity to aggregate. [3]  This pathway by which APP is cleaved is called amyloidogenic pathway. Under normal conditions, about 90% of secreted A  β  peptides are A  β 40 , which is a soluble form of the peptide that only slowly converts to an insoluble β -sheet configuration and thus can be eliminated from the brain. In contrast, about 10% of secreted A  β  peptides are  A  β 42 , species that are highly fibrillogenic and deposited early in individuals with AD and Down’s syndrome. Intracellular assembly states of A  β  are monomers, oligomers, protofibrils, and fibrils. The monomeric species are not pathological, however the nucleation dependent fibril formation related to protein misfolding makes the A  β  toxic. The oligomeric and protofibrillar species may facilitate tau hyperphosphorylation, disruption of proteasome and mitochondria function, dysregulation of calcium homeostasis, synaptic failure and cognitive dysfunction [4,5]  [Figure 1]. TAU HYPOTHESIS The tau hypothesis states that excessive or abnormal phosphorylation of tau results in the transformation of normal adult tau into PHF-tau (paired helical filament) and NFTs. Tau protein is a highly soluble microtubule-associated protein (MAP). Through its isoforms and phosphorylation tau protein interacts with tubulin to stabilize microtubule assembly. Tau proteins constitute a family of six isoforms  with the range from 352-441 amino acids. The longest isoform in the CNS has four repeats (R1, R2, R3, and R4) and two inserts (441 amino acids total), whereas the shortest isoform has three repeats (R1, R3, and R4) and no insert (352 amino acids total). All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments from AD. Figure 1 :  Amyloid cascade hypothesis Mohandas, et al. : Neurobiology of Alzheimer’s disease  Indian J Psychiatry 51(1), Jan-Mar 2009 57 Mutations that alter function and isoform expression of tau lead to hyperphosphorylation. The process of tau aggregation in the absence of mutations is not known but might result from increased phosphorylation, protease action or exposure to polyanions, such as glycosaminoglycans. [6]  Hyperphosphorylated tau disassembles microtubules and sequesters normal tau, MAP 1(microtubule associated protein1), MAP 2, and ubiquitin into tangles of PHFs. This insoluble structure damages cytoplasmic functions and interferes with axonal transport,  which can lead to cell death. [7]  [Figure 2] INFLAMMATORY HYPOTHESIS Microglia, astrocytes and possibly to a lesser extent the neurons are involved in the inflammatory process in AD.  A  β  can activate microglia which leads to an increase in cell surface expression of major histocompatibility complex II (MHC II) along with increased secretion of the pro-inflammatory cytokines interleukin-1 β  (IL-1 β ), interleukin-6 (IL-6), and tumor necrosis factor α  (TNF α ) as well as the chemokines- interleukin-8 (IL-8), macrophage inflammatory protein-1 α  (MIP-1 α ), and monocyte chemo-attractant protein-1. [8]  A  β  also induces a phagocytic response in microglia and expression of nitric oxide synthase (NOS) resulting in neuronal damage. [9]  Microglia may also play a role in the degradation of A  β  by the release of insulin degrading enzyme (IDE).  Astrocytes also cluster at sites of A  β  deposits and secrete interleukins, prostaglandins, leukotrienes, thromboxanes, coagulation factors, and protease inhibitors. Neurons themselves are able to express significantly higher levels of classical pathway complement and pro-inflammatory products that trigger inflammatory processes. Further, the complement system, cytokines, chemokines, and acute phase proteins (especially pentraxins) contribute to the inflammatory response in AD. The neuroinflammation as a primary cause or secondary effect in Alzheimerogenesis is a chicken and egg question. [10] OXIDATIVE STRESS HYPOTHESIS Reactive oxygen species (ROS or free radicals) the major portion of which (95-98%) comes from the byproducts of the electron transport chain (ETC) of the mitochondria, may mediate oxidative cell injury and cell death. [11]  Mitochondrial oxidative phosphorylation is the major source of free radicals like the hydrogen peroxide radicals (H 2 O 2 ), hydroxyl radicals (OH . ) and the superoxide radical (O 2-. ). The oxidative damage that ensues is seen in lipids, proteins, nucleic acids, and sugars all of which are organic compounds essential for the structural and functional integrity of neurons. [12]  In AD, there is inhibition of ETC resulting in the accumulation of electrons in the complex I and coenzyme Q (CoQ). The electrons therein accumulated can be donated directly to molecular oxygen to form the superoxide radical (O 2 - . ). The superoxide radical (O 2 - . ) can react with nitric oxide to form peroxynitrate radical (OONO - ). The H 2 O 2 in the presence of transition metals is converted to the toxic hydroxyl (OH . ) radical. Therefore, AD is associated with dysfunction of the ETC and free radical production. AD is also characterized by a deficiency of antioxidant capacity. The activities of the enzymes Cu/Zn SOD (superoxide dismutase) are reduced and there is a deficiency of glutathione (GSH). The free radicals thus are able to produce cellular damage unchecked by antioxidants. [13]  ROS mediated DNA oxidation causes strand breaks, DNA-protein cross linking and base modification. Glyco-oxidation by ROS results in the formation of advanced glycation end products (AGEs). AGE modified protein can produce more ROS. There is direct biochemical link between AGEs and lipid peroxidation leading to further advancement of AD pathology. [13] The mitochondrial hypothesis, the hydrogen peroxide hypothesis and the amyloid beta synergistic endothelial and neuronal toxicity (ABSENT) hypothesis revolve around ROS mediated neuronal dysfunction either directly or indirectly. VASCULAR HYPOTHESIS The vascular hypothesis proposes that AD develops when two biological events converge namely advancing age and the presence of vascular risk factors for AD. Epidemiological data exist implicating vascular risk factors in AD. Shared risk factors in both AD and vascular dementia and the response to pharmacotherapy targeting vascular factors benefiting AD are additional findings. Cerebral microvascular pathology Figure 2 :  Tau hypothesis Mohandas, et al. : Neurobiology of Alzheimer’s disease Hyperphosphorylation mutation  Indian J Psychiatry 51(1), Jan-Mar 2009 58 and cerebral hypoperfusion may trigger the cognitive and degenerative changes in AD. Advancing age and the presence of vascular risk factors create a critically attained threshold of cerebral hypoperfusion (CATCH). CATCH is an unremitting and progressive pathology affecting cerebral capillaries. When CATCH is reached, there is dysregulation of endothelial nitric oxide (NO) production leading to capillary degeneration. This along with the lowered ATP or energy supply leads to mitochondrial oxidative stress. The resulting crisis leads to cellular and subcellular pathology involving protein synthesis, development of plaques, inflammatory response, and synaptic damage leading to the manifestations of AD [14] [Figure 3]. CHOLESTEROL HYPOTHESIS Hypercholesterolaemia is a modifiable risk factor in AD.  ApoE is the major apolipoprotein in the brain, modifies the age of onset for AD. Apolipoprotein E4 (ApoE4) is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. It is a target gene of liver X receptor, a nuclear receptor member that play role in metabolism of cholesterol, fatty acid, and glucose homeostasis. ApoE4 homozygotes have a mean age of onset of <70 years compared to >80  years for ApoE3 homozygotes. In contrast, inheritance of one ApoE2 allele delays the age of onset of AD to >90  years. [15]  The precise mechanisms by which ApoE participates in AD pathogenesis remain largely undefined. Several hypotheses are proposed to explain the same they include (a) the proposed role of ApoE to mediate neuroinflammation, (b) its participation in the regulation of the cholinergic neurotransmitter system, (c) its role in neuronal signaling, and (d) ApoEs maintenance of the integrity of the blood–brain barrier. However, the most prominent hypotheses of  ApoE function is its key role as a mediator of A  β  metabolism.  ApoE binds A  β , affects the deposition and clearance of A  β , and is required for amyloid deposition. Furthermore, ApoE affects amyloid deposition in an allele-specific manner. However, the exact pathophysiologic process is yet to be elucidated. [16] The role of cholesterol in the pathology of AD is also shown by the ability of statins to reduce the prevalence of AD by up to 70%. Similarly, inhibition of cholesterol biosynthesis by statins and another cholesterol synthesis inhibitor was found to reduce amyloid burden in guinea pigs and murine models of AD. However, several prospective studies have demonstrated that statins reduce the turnover of brain cholesterol at standard therapeutic doses, although the steady-state levels of A  β  in the cerebrospinal fluid (CSF) remain unaltered. The role of statins in AD is still a subject for further investigation. [17] The role of cholesterol is further brought to the fore by the fact that intracellular cholesterol may regulate APP processing by directly modulating secretase activity or by affecting the intracellular trafficking of secretases and/ or APP. Cholesterol loading increases γ -secretase activity and amyloidogenic pathway while low intracellular cholesterol favors non-amyloidogenic pathway. There are also genetic factors linking cholesterol metabolism and  AD, though ApoE is the only gene with replicable evidence, several candidate genes involved in lipid metabolism like  A2M (alpha-2-Macroglobulin), LRP (lipoprotein receptor related protein), IDE (insulin degrading enzyme), ABCA1 (ATP-binding cassette transporter), ACAT (Acyl-CoA cholesteryl acyl transferase), CYP 46 (Cytochrome P450, family 46, convertscholesterol to 24S-hydroxycholesterol) are being investigated for putative roles with mixed results. [17]  Biochemical and pharmacological evidence strongly support a role for cholesterol and lipid metabolism in A  β  generation, deposition, and clearance. With the exception of ApoE, further candidate genes need to be identified. [17] METALLOBIOLOGY High levels of copper (Cu), iron (Fe), and zinc (Zn) are seen in the amyloid plaques and both A  β  and APP have metal ion binding sites. Micromolecular concentrations of Zn 2+  can result in the precipitation of β  amyloid at physiologic pH. Age dependent hyperactivity of the ZnT3 transporter in females accounts for the increased incidence of AD. A  β Cu   complexes and plaques that are bound to Zn may reduce H 2 O 2  production and resultant toxicity than soluble amyloids that are not bound to Zn. [18] Micromolecular concentrations of Cu and Fe on the other hand precipitate β  amyloid at slightly acidic pH. Cu and Fe are also co-factors to β  amyloid in the generation of oxidative stress. A  β  via its binding to Cu 2+  (A  β Cu 2+ ) and Fe 3+  (A  β  Fe 3+ ) converts them to Cu + and Fe 2+ , respectively and this is followed by the generation of H 2 O 2  by double electron transfer to oxygen. This generation of H 2 O 2  creates the ideal milieu for the generation of highly reactive hydroxyl radicals (OH . ) (Fenton reaction). A  β Cu 2+ is oxidized by H 2 O 2 to form   cross-linked and soluble forms of A  β . Oxidized A  β  oligomers are resistant to proteolysis and they are likely to become subunits for Zn 2+  induced assembly to amyloid mass. [18] Figure 3 :  Vascular hypothesis Mohandas, et al. : Neurobiology of Alzheimer’s disease
We Need Your Support
Thank you for visiting our website and your interest in our free products and services. We are nonprofit website to share and download documents. To the running of this website, we need your help to support us.

Thanks to everyone for your continued support.

No, Thanks