Skip to main content
SpringerLink
Log in

Neurobiological Mechanisms Involved in the Pathogenesis of Alzheimer’s Disease

  • Chapter
  • First Online:
Biological, Diagnostic and Therapeutic Advances in Alzheimer's Disease

Abstract

Alzheimer’s disease (AD) is one of the many neurodegenerative disorders which is characterized by progressive loss of neurons due to the extracellular accumulation of misprocessed and aggregated amyloid beta (Aβ)-plaques and appearance of intracellular neurofibrillary tangles containing hyperphosphorylated tau protein which ultimately leads to loss of synapses and cognitive decline. Aggregation of amyloid beta (Aβ)-plaques is the hallmark of AD. Aβ is the proteolytic cleavage product of amyloid precursor protein (APP) which is cleaved by β- and γ-secretase enzymes into Aβ1–42 and Aβ1–40 isoforms where the former readily aggregate more rapidly than the latter. Tau protein, the major component of neurofibrillary tangles, is a microtubule-associated protein which is usually soluble but becomes insoluble as it forms tangles of oligomers which is thought to be initiated by toxic concentrations of Aβ-plaques. Recent studies have shown that some genetic mutations, genomic instability and other factors like head injuries, depression, imbalanced diet and age progression all contribute to the development and progression of AD. The most important gene, for which a role in ageing-related late-onset AD has been established since a decade, is APOE where different variants of the gene differently predispose the individuals to the development of AD. In this chapter, we will be highlighting well-established molecular and cellular mechanisms behind the development and progression of AD, the regions in the brain that are affected and the known genetic basis behind the onset and pathophysiology of AD. In the later section, we will address some of the current and prospective therapeutic interventions based on our current understanding of neurobiological mechanisms underlying AD.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Ansari MA et al (2006) In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: relevance to Alzheimer’s disease and other oxidative stress-related neurodegenerative disorders. Free Radic Biol Med 41(11):1694–1703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Association, A.s (2018) 2018 Alzheimer’s disease facts and figures. Alzheimers Dement 14(3):367–429

    Article  Google Scholar 

  • Atwood CS et al (2003) Amyloid-beta: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-beta. Brain Res Brain Res Rev 43(1):1–16

    Article  CAS  PubMed  Google Scholar 

  • Avila J et al (2004) Role of tau protein in both physiological and pathological conditions. Physiol Rev 84(2):361–384

    Article  CAS  PubMed  Google Scholar 

  • Baas PW, Qiang L (2005) Neuronal microtubules: when the MAP is the roadblock. Trends Cell Biol 15(4):183–187

    Article  CAS  PubMed  Google Scholar 

  • Baloh RH et al (2007) Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations. J Neurosci 27(2):422–430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baudier J, Cole RD (1988) Interactions between the microtubule-associated tau proteins and S100b regulate tau phosphorylation by the Ca2+/calmodulin-dependent protein kinase II. J Biol Chem 263(12):5876–5883

    CAS  PubMed  Google Scholar 

  • Block ML (2008) NADPH oxidase as a therapeutic target in Alzheimer’s disease. BMC Neurosci 9(Suppl 2):S8

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bobinski M et al (1996) Neurofibrillary pathology–correlation with hippocampal formation atrophy in Alzheimer disease. Neurobiol Aging 17(6):909–919

    CAS  PubMed  Google Scholar 

  • Bonda DJ et al (2010) Mitochondrial dynamics in Alzheimer’s disease: opportunities for future treatment strategies. Drugs Aging 27(3):181–192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bowman AB et al (1999) Drosophila roadblock and Chlamydomonas LC7: a conserved family of dynein-associated proteins involved in axonal transport, flagellar motility, and mitosis. J Cell Biol 146(1):165–180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Braak H, Del Tredici K (2011) The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol 121(2):171–181

    Article  PubMed  Google Scholar 

  • Brown A (2003) Axonal transport of membranous and nonmembranous cargoes: a unified perspective. J Cell Biol 160(6):817–821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buee L et al (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 33(1):95–130

    Article  CAS  PubMed  Google Scholar 

  • Busser J, Geldmacher DS, Herrup K (1998) Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer’s disease brain. J Neurosci 18(8):2801–2807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Butterfield DA, Boyd-Kimball D (2018) Oxidative stress, amyloid-β peptide, and altered key molecular pathways in the pathogenesis and progression of Alzheimer’s disease. J Alzheimers Dis 62(3):1345–1367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Butterfield SM, Lashuel HA (2010) Amyloidogenic protein–membrane interactions: mechanistic insight from model systems. Angew Chem Int Ed 49(33):5628–5654

    Article  CAS  Google Scholar 

  • Butterfield DA et al (2001) Evidence of oxidative damage in Alzheimer’s disease brain: central role for amyloid beta-peptide. Trends Mol Med 7(12):548–554

    Article  CAS  PubMed  Google Scholar 

  • Butterfield DA et al (2006) Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer’s disease. Neurobiol Dis 22(2):223–232

    Article  CAS  PubMed  Google Scholar 

  • Butterfield DA et al (2007) Roles of amyloid β-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer’s disease and mild cognitive impairment. Free Radic Biol Med 43(5):658–677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Butterfield DA, Swomley AM, Sultana R (2013) Amyloid β-peptide (1–42)-induced oxidative stress in Alzheimer disease: importance in disease pathogenesis and progression. Antioxid Redox Signal 19(8):823–835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Canevari L, Clark JB, Bates TE (1999) β-Amyloid fragment 25–35 selectively decreases complex IV activity in isolated mitochondria. FEBS Lett 457(1):131–134

    Article  CAS  PubMed  Google Scholar 

  • Carrillo-Mora P, Luna R, Colin-Barenque L (2014) Amyloid beta: multiple mechanisms of toxicity and only some protective effects? Oxidative Med Cell Longev 2014:795375

    Article  CAS  Google Scholar 

  • Cash AD et al (2003) Microtubule reduction in Alzheimer’s disease and aging is independent of tau filament formation. Am J Pathol 162(5):1623–1627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cassagnes L-E et al (2013) The catalytically active copper-amyloid-Beta state: coordination site responsible for reactive oxygen species production. Angew Chem Int Ed 52(42):11110–11113

    Article  CAS  Google Scholar 

  • Castegna A et al (2004) Modulation of phospholipid asymmetry in synaptosomal membranes by the lipid peroxidation products, 4-hydroxynonenal and acrolein: implications for Alzheimer’s disease. Brain Res 1004(1–2):193–197

    Article  CAS  PubMed  Google Scholar 

  • Chalermpalanupap T et al (2013) Targeting norepinephrine in mild cognitive impairment and Alzheimer’s disease. Alzheimers Res Ther 5(2):21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang KA, Suh YH (2010) Possible roles of amyloid intracellular domain of amyloid precursor protein. BMB Rep 43(10):656–663

    Article  CAS  PubMed  Google Scholar 

  • Cheignon C et al (2018) Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol 14:450–464

    Article  CAS  PubMed  Google Scholar 

  • Chen Y et al (2016) Mitochondrial DNA rearrangement Spectrum in brain tissue of Alzheimer’s disease: analysis of 13 cases. PLoS One 11(6):e0154582

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chow VW et al (2010) An overview of APP processing enzymes and products. NeuroMolecular Med 12(1):1–12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cui JG et al (2007) Expression of inflammatory genes in the primary visual cortex of late-stage Alzheimer’s disease. Neuroreport 18(2):115–119

    Article  CAS  PubMed  Google Scholar 

  • de Paula VDJR et al (2009) Neurobiological pathways to Alzheimer’s disease: Amyloid-beta, TAU protein or both? Dementia & Neuropsychologia 3(3):188–194

    Article  Google Scholar 

  • Decker H et al (2010) Amyloid-beta peptide oligomers disrupt axonal transport through an NMDA receptor-dependent mechanism that is mediated by glycogen synthase kinase 3beta in primary cultured hippocampal neurons. J Neurosci 30(27):9166–9171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duering M et al (2005) Mean age of onset in familial Alzheimer’s disease is determined by amyloid beta 42. Neurobiol Aging 26(6):785–788

    Article  CAS  PubMed  Google Scholar 

  • Duff K et al (1996) Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 383(6602):710–713

    Article  CAS  PubMed  Google Scholar 

  • Ebbing B et al (2008) Effect of spastic paraplegia mutations in KIF5A kinesin on transport activity. Hum Mol Genet 17(9):1245–1252

    Article  CAS  PubMed  Google Scholar 

  • Eckert A et al (2010) Convergence of amyloid-beta and tau pathologies on mitochondria in vivo. Mol Neurobiol 41(2–3):107–114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eckman CB, Eckman EA (2007) An update on the amyloid hypothesis. Neurol Clin 25(3):669–682

    Article  PubMed  PubMed Central  Google Scholar 

  • Edwards DR, Handsley MM, Pennington CJ (2008) The ADAM metalloproteinases. Mol Asp Med 29(5):258–289

    Article  CAS  Google Scholar 

  • Farrer MJ et al (2009) DCTN1 mutations in Perry syndrome. Nat Genet 41(2):163–165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ferreira A, Caceres A, Kosik KS (1993) Intraneuronal compartments of the amyloid precursor protein. J Neurosci 13(7):3112–3123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gao HM et al (2002) Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson’s disease. J Neurochem 81(6):1285–1297

    Article  CAS  PubMed  Google Scholar 

  • García-Escudero V et al (2013) Deconstructing mitochondrial dysfunction in Alzheimer disease. Oxidative Med Cell Longev 2013:13, Article Id 162152

    Google Scholar 

  • German DC et al (1992) Disease-specific patterns of locus coeruleus cell loss. Ann Neurol 32(5):667–676

    Article  CAS  PubMed  Google Scholar 

  • Gibson GE et al (2012) Deficits in the mitochondrial enzyme α-ketoglutarate dehydrogenase lead to Alzheimer’s disease-like calcium dysregulation. Neurobiology of aging 33(6):1121.e13–1121.e24

    Article  CAS  Google Scholar 

  • Glabe CC (2005) Amyloid accumulation and pathogenesis of Alzheimer’s disease: significance of monomeric, oligomeric and fibrillar Abeta. Subcell Biochem 38:167–177

    Article  CAS  PubMed  Google Scholar 

  • Godoy JA et al (2014) Signaling pathway cross talk in Alzheimer’s disease. Cell Commun Signal 12(1):23

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Goldstein LS, Yang Z (2000) Microtubule-based transport systems in neurons: the roles of kinesins and dyneins. Annu Rev Neurosci 23:39–71

    Article  CAS  PubMed  Google Scholar 

  • Gong CX, Grundke-Iqbal I, Iqbal K (1994) Dephosphorylation of Alzheimer’s disease abnormally phosphorylated tau by protein phosphatase-2A. Neuroscience 61(4):765–772

    Article  CAS  PubMed  Google Scholar 

  • Gouras GK et al (1998) Generation and regulation of beta-amyloid peptide variants by neurons. J Neurochem 71(5):1920–1925

    Article  CAS  PubMed  Google Scholar 

  • Grimm M, Hartmann T (2012) Recent understanding of the molecular mechanisms of Alzheimer’s disease. J Addict Res Ther 5:1–27

    Google Scholar 

  • Grudzien A et al (2007) Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer’s disease. Neurobiol Aging 28(3):327–335

    Article  CAS  PubMed  Google Scholar 

  • Grundke-Iqbal I et al (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A 83(13):4913–4917

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gunawardena S, Goldstein LS (2001) Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila. Neuron 32(3):389–401

    Article  CAS  PubMed  Google Scholar 

  • Gunawardena S, Goldstein LS (2004) Cargo-carrying motor vehicles on the neuronal highway: transport pathways and neurodegenerative disease. J Neurobiol 58(2):258–271

    Article  CAS  PubMed  Google Scholar 

  • Gupta A, Goyal R (2016) Amyloid beta plaque: a culprit for neurodegeneration. Acta Neurol Belg 116(4):445–450

    Article  PubMed  Google Scholar 

  • Hanger DP, Seereeram A, Noble W (2009) Mediators of tau phosphorylation in the pathogenesis of Alzheimer’s disease. Expert Rev Neurother 9(11):1647–1666

    Article  CAS  PubMed  Google Scholar 

  • Hardy J, Allsop D (1991) Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 12:383–388

    Article  CAS  PubMed  Google Scholar 

  • Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580):353–356

    Article  CAS  PubMed  Google Scholar 

  • Heneka MT et al (2010) Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci U S A 107(13):6058–6063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Herzog AG, Kemper TL (1980) Amygdaloid changes in aging and dementia. Arch Neurol 37(10):625–629

    Article  CAS  PubMed  Google Scholar 

  • Higuchi M, Lee VM, Trojanowski JQ (2002) Tau and axonopathy in neurodegenerative disorders. NeuroMolecular Med 2(2):131–150

    Article  CAS  PubMed  Google Scholar 

  • Hirokawa N (1998) Kinesin and dynein superfamily proteins and the mechanism of organelle transport. Science 279(5350):519–526

    Article  CAS  PubMed  Google Scholar 

  • Hiruma H et al (2003) Glutamate and amyloid beta-protein rapidly inhibit fast axonal transport in cultured rat hippocampal neurons by different mechanisms. J Neurosci 23(26):8967–8977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hodgkin AL, Huxley AF (1939) Action potentials recorded from inside a nerve fibre. Nature 144:710

    Article  Google Scholar 

  • Huang X et al (1999) Cu(II) potentiation of alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem 274(52):37111–37116

    Article  CAS  PubMed  Google Scholar 

  • Ito S et al (2007) Cerebral clearance of human amyloid-β peptide (1–40) across the blood–brain barrier is reduced by self-aggregation and formation of low-density lipoprotein receptor-related protein-1 ligand complexes. J Neurochem 103(6):2482–2490

    Article  CAS  PubMed  Google Scholar 

  • Ittner LM et al (2010) Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 142(3):387–397

    Article  CAS  PubMed  Google Scholar 

  • Jeynes B, Provias J (2008) Evidence for altered LRP/RAGE expression in Alzheimer lesion pathogenesis. Curr Alzheimer Res 5(5):432–437

    Article  CAS  PubMed  Google Scholar 

  • Jobst KA et al (1992) Detection in life of confirmed Alzheimer’s disease using a simple measurement of medial temporal lobe atrophy by computed tomography. Lancet 340(8829):1179–1183

    Article  CAS  PubMed  Google Scholar 

  • Jobst KA et al (1994) Rapidly progressing atrophy of medial temporal lobe in Alzheimer’s disease. Lancet 343(8901):829–830

    Article  CAS  PubMed  Google Scholar 

  • Jomova K et al (2010) Metals, oxidative stress and neurodegenerative disorders. Mol Cell Biochem 345(1–2):91–104

    Article  CAS  PubMed  Google Scholar 

  • Kamal A et al (2001) Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature 414(6864):643–648

    Article  CAS  PubMed  Google Scholar 

  • Kayed R et al (2003) Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300(5618):486–489

    Article  CAS  PubMed  Google Scholar 

  • Kelleher RJ 3rd, Shen J (2017) Presenilin-1 mutations and Alzheimer’s disease. Proc Natl Acad Sci U S A 114(4):629–631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ko SY et al (2015) The possible mechanism of advanced Glycation end products (AGEs) for Alzheimer’s disease. PLoS One 10(11):e0143345

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Koo EH et al (1990) Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proc Natl Acad Sci U S A 87(4):1561–1565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kowalska A (2004) Genetic aspects of amyloid beta-protein fibrillogenesis in Alzheimer’s disease. Folia Neuropathol 42(4):235–237

    CAS  PubMed  Google Scholar 

  • Lal R, Lin H, Quist AP (2007) Amyloid beta ion channel: 3D structure and relevance to amyloid channel paradigm. Biochim Biophys Acta 1768(8):1966–1975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee VM, Daughenbaugh R, Trojanowski JQ (1994) Microtubule stabilizing drugs for the treatment of Alzheimer’s disease. Neurobiol Aging 15(Suppl 2):S87–S89

    Article  PubMed  Google Scholar 

  • Lee M-C et al (2018) Zinc ion rapidly induces toxic, off-pathway amyloid-β oligomers distinct from amyloid-β derived diffusible ligands in Alzheimer’s disease. Sci Rep 8(1):4772

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Li Y et al (2012) Analysis of hippocampal gene expression profile of Alzheimer’s disease model rats using genome chip bioinformatics. Neural Regen Res 7(5):332–340

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liang WS et al (2008) Altered neuronal gene expression in brain regions differentially affected by Alzheimer’s disease: a reference data set. Physiol Genomics 33(2):240–256

    Article  CAS  PubMed  Google Scholar 

  • Lin H, Bhatia R, Lal R (2001) Amyloid β protein forms ion channels: implications for Alzheimer’s disease pathophysiology. FASEB J 15(13):2433–2444

    Article  CAS  PubMed  Google Scholar 

  • Lindwall G, Cole RD (1984) Phosphorylation affects the ability of tau protein to promote microtubule assembly. J Biol Chem 259(8):5301–5305

    CAS  PubMed  Google Scholar 

  • Liu F et al (2002) Role of glycosylation in hyperphosphorylation of tau in Alzheimer’s disease. FEBS Lett 512(1–3):101–106

    Article  CAS  PubMed  Google Scholar 

  • Lloret A et al (2011) Amyloid-beta toxicity and tau hyperphosphorylation are linked via RCAN1 in Alzheimer’s disease. J Alzheimers Dis 27(4):701–709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lopez-Toledano MA, Shelanski ML (2004) Neurogenic effect of beta-amyloid peptide in the development of neural stem cells. J Neurosci 24(23):5439–5444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luo Y et al (2003) BACE1 (β-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time. Neurobiol Dis 14(1):81–88

    Article  CAS  PubMed  Google Scholar 

  • Luxenberg JS et al (1987) Rate of ventricular enlargement in dementia of the Alzheimer type correlates with rate of neuropsychological deterioration. Neurology 37(7):1135–1140

    Article  CAS  PubMed  Google Scholar 

  • Magistretti PJ, Allaman I (2015) A cellular perspective on brain energy metabolism and functional imaging. Neuron 86(4):883–901

    Article  CAS  PubMed  Google Scholar 

  • Magrane J et al (2005) Intraneuronal beta-amyloid expression downregulates the Akt survival pathway and blunts the stress response. J Neurosci 25(47):10960–10969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mark RJ et al (1997) A role for 4-hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid beta-peptide. J Neurochem 68(1):255–264

    Article  CAS  PubMed  Google Scholar 

  • Markesbery WR (1997) Oxidative stress hypothesis in Alzheimer’s disease. Free Radic Biol Med 23(1):134–147

    Article  CAS  PubMed  Google Scholar 

  • Martin M et al (1999) Cytoplasmic dynein, the dynactin complex, and kinesin are interdependent and essential for fast axonal transport. Mol Biol Cell 10(11):3717–3728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsuda S et al (2001) c-Jun N-terminal kinase (JNK)-interacting protein-1b/islet-brain-1 scaffolds Alzheimer’s amyloid precursor protein with JNK. J Neurosci 21(17):6597–6607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matthews FE et al (2013) A two-decade comparison of prevalence of dementia in individuals aged 65 years and older from three geographical areas of England: results of the Cognitive Function and Ageing Study I and II. Lancet (London, England) 382(9902):1405–1412

    Article  Google Scholar 

  • Mattson MP, Gleichmann M, Cheng A (2008) Mitochondria in neuroplasticity and neurological disorders. Neuron 60(5):748–766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mc Donald JM et al (2015) The aqueous phase of Alzheimer’s disease brain contains assemblies built from approximately 4 and approximately 7 kDa Abeta species. Alzheimers Dement 11(11):1286–1305

    Article  PubMed  PubMed Central  Google Scholar 

  • McInnes J (2013) Insights on altered mitochondrial function and dynamics in the pathogenesis of neurodegeneration. Transl Neurodegener 2(1):12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meda L et al (1995) Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 374(6523):647–650

    Article  CAS  PubMed  Google Scholar 

  • Miller KR, Streit WJ (2007) The effects of aging, injury and disease on microglial function: a case for cellular senescence. Neuron Glia Biol 3(3):245–253

    Article  PubMed  Google Scholar 

  • Miller DL et al (1993) Peptide compositions of the cerebrovascular and senile plaque core amyloid deposits of Alzheimer’s disease. Arch Biochem Biophys 301(1):41–52

    Article  CAS  PubMed  Google Scholar 

  • Misko A et al (2010) Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex. J Neurosci 30(12):4232–4240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Montoliu-Gaya L, Villegas S (2015) Protein structures in Alzheimer’s disease: the basis for rationale therapeutic design. Arch Biochem Biophys 588:1–14

    Article  CAS  PubMed  Google Scholar 

  • Moreira PI (2018) Sweet mitochondria: a shortcut to Alzheimer’s disease. J Alzheimers Dis 62(3):1391–1401

    Article  PubMed  PubMed Central  Google Scholar 

  • Morfini G et al (2002) Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility. EMBO J 21(3):281–293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morfini GA et al (2009) Axonal transport defects in neurodegenerative diseases. J Neurosci 29(41):12776–12786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mudher A, Lovestone S (2002) Alzheimer’s disease-do tauists and baptists finally shake hands? Trends Neurosci 25(1):22–26

    Article  CAS  PubMed  Google Scholar 

  • Muresan Z, Muresan V (2005) Coordinated transport of phosphorylated amyloid-beta precursor protein and c-Jun NH2-terminal kinase-interacting protein-1. J Cell Biol 171(4):615–625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Newsway V et al (2010) Perry syndrome due to the DCTN1 G71R mutation – a distinctive L-DOPA responsive disorder with behavioural syndrome, vertical gaze palsy and respiratory failure. Mov Disord 25(6):767–770

    Article  PubMed  PubMed Central  Google Scholar 

  • Noble W et al (2003) Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron 38(4):555–565

    Article  CAS  PubMed  Google Scholar 

  • Nunomura A et al (2009) RNA oxidation in Alzheimer disease and related neurodegenerative disorders. Acta Neuropathol 118(1):151–166

    Article  CAS  PubMed  Google Scholar 

  • O’Nuallain B et al (2010) Amyloid β-protein dimers rapidly form stable Synaptotoxic Protofibrils. J Neurosci 30(43):14411–14419

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ohshima Y et al (2018) Mutations in the β-amyloid precursor protein in familial Alzheimer’s disease increase Aβ oligomer production in cellular models. Heliyon 4(1):e00511–e00511

    Article  PubMed  PubMed Central  Google Scholar 

  • Omar RA et al (1999) Increased expression but reduced activity of antioxidant enzymes in Alzheimer’s disease. J Alzheimers Dis 1(3):139–145

    Article  CAS  PubMed  Google Scholar 

  • Perluigi M et al (2006a) In vivo protection by the xanthate tricyclodecan-9-yl-xanthogenate against amyloid beta-peptide (1-42)-induced oxidative stress. Neuroscience 138(4):1161–1170

    Article  CAS  PubMed  Google Scholar 

  • Perluigi M et al (2006b) In vivo protective effects of ferulic acid ethyl ester against amyloid-beta peptide 1-42-induced oxidative stress. J Neurosci Res 84(2):418–426

    Article  CAS  PubMed  Google Scholar 

  • Pietri M et al (2013) PDK1 decreases TACE-mediated alpha-secretase activity and promotes disease progression in prion and Alzheimer’s diseases. Nat Med 19(9):1124–1131

    Article  CAS  PubMed  Google Scholar 

  • Pigino G et al (2009) Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta. Proc Natl Acad Sci U S A 106(14):5907–5912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Plant LD et al (2003) The production of amyloid beta peptide is a critical requirement for the viability of central neurons. J Neurosci 23(13):5531–5535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Poulin SP et al (2011) Amygdala atrophy is prominent in early Alzheimer’s disease and relates to symptom severity. Psychiatry Res 194(1):7–13

    Article  PubMed  PubMed Central  Google Scholar 

  • Premkumar DR et al (1995) Induction of heme oxygenase-1 mRNA and protein in neocortex and cerebral vessels in Alzheimer’s disease. J Neurochem 65(3):1399–1402

    Article  CAS  PubMed  Google Scholar 

  • Prince M et al (2016) Recent global trends in the prevalence and incidence of dementia, and survival with dementia. Alzheimers Res Ther 8(1):23

    Article  PubMed  PubMed Central  Google Scholar 

  • Puls I et al (2003) Mutant dynactin in motor neuron disease. Nat Genet 33(4):455–456

    Article  CAS  PubMed  Google Scholar 

  • Qin L et al (2004) NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. J Biol Chem 279(2):1415–1421

    Article  CAS  PubMed  Google Scholar 

  • Rajendran R et al (2009) A novel approach to the identification and quantitative elemental analysis of amyloid deposits—insights into the pathology of Alzheimer’s disease. Biochem Biophys Res Commun 382(1):91–95

    Article  CAS  PubMed  Google Scholar 

  • Rissman RA et al (2004) Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. J Clin Invest 114(1):121–130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roher AE et al (1993) Beta-amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. Proc Natl Acad Sci U S A 90(22):10836–10840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rosales-Corral S et al (2004a) Kinetics of the neuroinflammation-oxidative stress correlation in rat brain following the injection of fibrillar amyloid-β onto the hippocampus in vivo. J Neuroimmunol 150(1–2):20–28

    Article  CAS  PubMed  Google Scholar 

  • Rosales-Corral S et al (2004b) Kinetics of the neuroinflammation-oxidative stress correlation in rat brain following the injection of fibrillar amyloid-beta onto the hippocampus in vivo. J Neuroimmunol 150(1–2):20–28

    Article  CAS  PubMed  Google Scholar 

  • Rui Y et al (2006) Acute impairment of mitochondrial trafficking by beta-amyloid peptides in hippocampal neurons. J Neurosci 26(41):10480–10487

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sadigh-Eteghad S et al (2014) Beta-amyloid exhibits antagonistic effects on alpha 7 nicotinic acetylcholine receptors in orchestrated manner. J Med Hypotheses Ideas 8(2):49–52

    Article  CAS  Google Scholar 

  • Sagare A et al (2007) Clearance of amyloid-β by circulating lipoprotein receptors. Nat Med 13:1029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Satizabal CL et al (2016) Incidence of dementia over three decades in the Framingham heart study. N Engl J Med 374(6):523–532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scahill RI et al (2002) Mapping the evolution of regional atrophy in Alzheimer’s disease: unbiased analysis of fluid-registered serial MRI. Proc Natl Acad Sci U S A 99(7):4703–4707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schilling T, Eder C (2011) Amyloid-beta-induced reactive oxygen species production and priming are differentially regulated by ion channels in microglia. J Cell Physiol 226(12):3295–3302

    Article  CAS  PubMed  Google Scholar 

  • Scott SA, DeKosky ST, Scheff SW (1991) Volumetric atrophy of the amygdala in Alzheimer’s disease: quantitative serial reconstruction. Neurology 41(3):351–356

    Article  CAS  PubMed  Google Scholar 

  • Scott SA et al (1992) Amygdala cell loss and atrophy in Alzheimer’s disease. Ann Neurol 32(4):555–563

    Article  CAS  PubMed  Google Scholar 

  • Selkoe DJ, Hardy J (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8(6):595–608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sengupta U, Nilson AN, Kayed R (2016) The role of amyloid-β oligomers in toxicity, propagation, and immunotherapy. EBioMedicine 6:42–49

    Article  PubMed  PubMed Central  Google Scholar 

  • Shankar GM et al (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14(8):837–842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sisodia SS, Tanzi RE (2007) Alzheimer’s disease: advances in genetics, molecular and cellular biology. Springer Science & Business Media, New York

    Book  Google Scholar 

  • Small DH, Mok SS, Bornstein JC (2001) Alzheimer’s disease and Abeta toxicity: from top to bottom. Nat Rev Neurosci 2(8):595–598

    Article  CAS  PubMed  Google Scholar 

  • Smith AD (2002) Imaging the progression of Alzheimer pathology through the brain. Proc Natl Acad Sci 99(7):4135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith KDB et al (2007) In vivo axonal transport rates decrease in a mouse model of Alzheimer’s disease. NeuroImage 35(4):1401–1408

    Article  PubMed  Google Scholar 

  • St George-Hyslop PH, Petit A (2005) Molecular biology and genetics of Alzheimer’s disease. C R Biol 328(2):119–130

    Article  CAS  PubMed  Google Scholar 

  • Stancu IC et al (2014) Models of beta-amyloid induced Tau-pathology: the long and “folded” road to understand the mechanism. Mol Neurodegener 9:51

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Steenland K et al (2016) A meta-analysis of Alzheimer’s disease incidence and prevalence comparing African-Americans and Caucasians. J Alzheimers Dis 50(1):71–76

    Article  PubMed  PubMed Central  Google Scholar 

  • Stokin GB et al (2005) Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307(5713):1282–1288

    Article  CAS  PubMed  Google Scholar 

  • Subramaniam R et al (1997) The lipid peroxidation product, 4-hydroxy-2-trans-nonenal, alters the conformation of cortical synaptosomal membrane proteins. J Neurochem 69(3):1161–1169

    Article  CAS  PubMed  Google Scholar 

  • Sun X, Chen WD, Wang YD (2015a) beta-Amyloid: the key peptide in the pathogenesis of Alzheimer’s disease. Front Pharmacol 6:221

    PubMed  PubMed Central  Google Scholar 

  • Sun X, Chen W-D, Wang Y-D (2015b) β-Amyloid: the key peptide in the pathogenesis of Alzheimer’s disease. Front Pharmacol 6:221

    PubMed  PubMed Central  Google Scholar 

  • Takashima A et al (1998) Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau. Proc Natl Acad Sci U S A 95(16):9637–9641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Talmat-Amar Y, Arribat Y, Parmentier M-L (2018) Vesicular axonal transport is modified in vivo by Tau deletion or overexpression in Drosophila. Int J Mol Sci 19(3):744

    Article  PubMed Central  CAS  Google Scholar 

  • Tang Y et al (2012) Early and selective impairments in axonal transport kinetics of synaptic cargoes induced by soluble amyloid beta-protein oligomers. Traffic 13(5):681–693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tarrade A et al (2006) A mutation of spastin is responsible for swellings and impairment of transport in a region of axon characterized by changes in microtubule composition. Hum Mol Genet 15(24):3544–3558

    Article  CAS  PubMed  Google Scholar 

  • Thal DR et al (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58(12):1791–1800

    Article  PubMed  Google Scholar 

  • Valko M, Morris H, Cronin MT (2005) Metals, toxicity and oxidative stress. Curr Med Chem 12(10):1161–1208

    Article  CAS  PubMed  Google Scholar 

  • Valla J, Berndt JD, Gonzalez-Lima F (2001) Energy hypometabolism in posterior cingulate cortex of Alzheimer’s patients: superficial laminar cytochrome oxidase associated with disease duration. J Neurosci 21(13):4923–4930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Varadarajan S et al (1999) Methionine residue 35 is important in amyloid beta-peptide-associated free radical oxidative stress. Brain Res Bull 50(2):133–141

    Article  CAS  PubMed  Google Scholar 

  • Varadarajan S et al (2001) Different mechanisms of oxidative stress and neurotoxicity for Alzheimer’s A beta(1–42) and A beta(25–35). J Am Chem Soc 123(24):5625–5631

    Article  CAS  PubMed  Google Scholar 

  • Vassar R et al (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286(5440):735–741

    Article  CAS  PubMed  Google Scholar 

  • Verhey KJ et al (2001) Cargo of kinesin identified as JIP scaffolding proteins and associated signaling molecules. J Cell Biol 152(5):959–970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vershinin M et al (2007) Multiple-motor based transport and its regulation by Tau. Proc Natl Acad Sci U S A 104(1):87–92

    Article  CAS  PubMed  Google Scholar 

  • Vetrivel KS et al (2004) Association of gamma-secretase with lipid rafts in post-Golgi and endosome membranes. J Biol Chem 279(43):44945–44954

    Article  CAS  PubMed  Google Scholar 

  • Vetrivel KS et al (2005) Spatial segregation of gamma-secretase and substrates in distinct membrane domains. J Biol Chem 280(27):25892–25900

    Article  CAS  PubMed  Google Scholar 

  • Vicario-Orri E, Opazo CM, Munoz FJ (2015) The pathophysiology of axonal transport in Alzheimer’s disease. J Alzheimers Dis 43(4):1097–1113

    Article  CAS  PubMed  Google Scholar 

  • Violet M et al (2015) Prefibrillar Tau oligomers alter the nucleic acid protective function of Tau in hippocampal neurons in vivo. Neurobiol Dis 82:540–551

    Article  CAS  PubMed  Google Scholar 

  • Vogt BA, Crino PB, Vogt LJ (1992) Reorganization of cingulate cortex in Alzheimer’s disease: neuron loss, neuritic plaques, and muscarinic receptor binding. Cereb Cortex 2(6):526–535

    Article  CAS  PubMed  Google Scholar 

  • Walsh DM, Selkoe DJ (2007) A beta oligomers – a decade of discovery. J Neurochem 101(5):1172–1184

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Mandelkow E (2016) Tau in physiology and pathology. Nat Rev Neurosci 17(1):5–21

    Article  PubMed  CAS  Google Scholar 

  • Wang X et al (2010) Amyloid-beta-derived diffusible ligands cause impaired axonal transport of mitochondria in neurons. Neurodegener Dis 7(1–3):56–59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X et al (2014) Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochim Biophys Acta 1842(8):1240–1247

    Article  CAS  PubMed  Google Scholar 

  • Wasco W et al (1993) Isolation and characterization of APLP2 encoding a homologue of the Alzheimer’s associated amyloid beta protein precursor. Nat Genet 5(1):95–100

    Article  CAS  PubMed  Google Scholar 

  • Wildsmith KR et al (2013) Evidence for impaired amyloid beta clearance in Alzheimer’s disease. Alzheimers Res Ther 5(4):33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilquet V, De Strooper B (2004) Amyloid-beta precursor protein processing in neurodegeneration. Curr Opin Neurobiol 14(5):582–588

    Article  CAS  PubMed  Google Scholar 

  • Wirths O et al (2006) Axonopathy in an APP/PS1 transgenic mouse model of Alzheimer’s disease. Acta Neuropathol 111(4):312–319

    Article  CAS  PubMed  Google Scholar 

  • Wu DC et al (2003) NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. Proc Natl Acad Sci U S A 100(10):6145–6150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu L-L et al (2017) Mitochondrial dynamics changes with age in an APPsw/PS1dE9 mouse model of Alzheimer’s disease. Neuroreport 28(4):222–228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu F et al (2018) KIF1Bβ mutations detected in hereditary neuropathy impair IGF1R transport and axon growth. The Journal of Cell Biology 217:3480–3496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yagishita S (1978) Morphological investigations on axonal swellings and spheroids in various human diseases. Virchows Arch A Pathol Anat Histol 378(3):181–197

    Article  CAS  PubMed  Google Scholar 

  • Yankner B, Duffy L, Kirschner D (1990) Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science 250(4978):279–282

    Article  CAS  PubMed  Google Scholar 

  • Yatin SM, Aksenov M, Butterfield DA (1999) The antioxidant vitamin E modulates amyloid beta-peptide-induced creatine kinase activity inhibition and increased protein oxidation: implications for the free radical hypothesis of Alzheimer’s disease. Neurochem Res 24(3):427–435

    Article  CAS  PubMed  Google Scholar 

  • Zarow C et al (2003) Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol 60(3):337–341

    Article  PubMed  Google Scholar 

  • Zhang H et al (2012) Proteolytic processing of Alzheimer’s beta-amyloid precursor protein. J Neurochem 120(Suppl 1):9–21

    Article  CAS  PubMed  Google Scholar 

  • Zhao C et al (2001) Charcot-Marie-tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. Cell 105(5):587–597

    Article  CAS  PubMed  Google Scholar 

  • Zhu N et al (2015) Huperzine A protects neural stem cells against Abeta-induced apoptosis in a neural stem cells and microglia co-culture system. Int J Clin Exp Pathol 8(6):6425–6433

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Life Sciences, Jawaharlal Nehru University, New Delhi, Delhi, India

    Fayaz Ahmad Mir

  2. Centre for Microbial Ecology, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India

    Zaigham Abbas Rizvi

Authors
  1. Fayaz Ahmad Mir
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zaigham Abbas Rizvi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zaigham Abbas Rizvi .

Editor information

Editors and Affiliations

  1. King Fahd Medical Research Center, King Abdulaziz University Jeddah, Saudi Arabia, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia

    Ghulam Md Ashraf

  2. Novel Global Community Educational Foundation, Hebersham, NSW, Australia, AFNP Med, Wien, Austria

    Athanasios Alexiou

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Mir, F.A., Rizvi, Z.A. (2019). Neurobiological Mechanisms Involved in the Pathogenesis of Alzheimer’s Disease. In: Ashraf, G., Alexiou, A. (eds) Biological, Diagnostic and Therapeutic Advances in Alzheimer's Disease. Springer, Singapore. https://doi.org/10.1007/978-981-13-9636-6_13

Download citation

Publish with us

Policies and ethics

Search

Navigation