Cellular and molecular mechanisms of brain aging
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Cellular and molecular mechanisms of brain aging






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Cellular and molecular mechanisms of brain aging Cellular and molecular mechanisms of brain aging Presentation Transcript

  • Neurodegenerative disease April 2008
  • Pt. 4 Major categories of neurologic disease 527 30 Disturbances of cerebrospinal fluid and its circulation 529 31 Intracranial neoplasms and paraneoplastic disorders 546 32 Infections of the nervous system (bacterial, fungal, spirochetal, parasitic) and sarcoidosis 592 33 Viral infections of the nervous system, chronic meningitis, and prion diseases 631 34 Cerebrovascular diseases 660 35 Craniocerebral trauma 747 36 Multiple sclerosis and allied demyelinative diseases 771 37 The inherited metabolic diseases of the nervous system 797 38 Developmental diseases of the nervous system 850 39 Degenerative diseases of the nervous system 895 40 The acquired metabolic disorders of the nervous system 959 41 Diseases of the nervous system due to nutritional deficiency-983 42 Alcohol and alcoholism 1004 43 Disorders of the nervous system due to drugs, toxins, and other chemical agents-1016
  • Characteristics of neurodegenerative disease
    • Insidious in onset
    • Progressive course
    • Selective death/dysfunction of neurons
  • Characteristics of neurodegenerative disease
    • Insidious in onset
    • Progressive course
    • Selective death/dysfunction of neurons
    • Etiology unclear
  • Examples of neurodegenerative disease:
    • Alzheimer’s disease
    • Parkinson’s disease
    • Frontotemporal dementia
    • Amyotrophic lateral sclerosis (Lou Gehrig’s disease)
    • Spinocerebellar ataxia
    • Huntington’s disease
  • Neurodegenerative disease is common
  • Neurodegenerative disease prevalence:
    • Alzheimer’s disease:
      • 1-2% age 65-75; 50% over age 85
    • Parkinson’s disease
      • 13/100,00; 0.5-1% age 60-69; 1-3% over age 80
    • Frontotemporal dementia
      • 1 per 10,000?
    • ALS
      • 1-2 per 100,000 per year
    • Spinocerebellar ataxias
      • 0.3-3 per 100,000
    • Huntington’s disease
      • 1 in 10,000
  • Organization of presentation:
    • Clinical presentation and diagnosis
    • Pathology
    • Genetic risk factors
    • Environmental risk factors
    • Pathogenesis (stories we tell)
    • Treatments available (ie, the need for better treatments)
  • Alzheimer’s presentation
    • Starts with memory loss--repetitive stories, repetitive questions, forgotten events, progressing to the point that ADLs are affected.
    • By the time of diagnosis, a second “cognitive domain” is affected (language, spatial function, executive dysfunction)
  • Alzheimer’s course:
    • Progressive loss of cognitive abilities and ADLs, leading ultimately to a vegetative state, and finally death (infection, malnutrition, MI, CVA)
    • Average time from dx to death = 8-10 years
    • Rate of progression is variable
    • Behavior changes (psychosis, depression, apathy, agitation) are especially variable
    • “ If you’ve met one patient with Alzheimer’s……you’ve met one patient with Alzheimer’s”
  • Alzheimer’s pathology
    • Amyloid plaques
    • Neurofibrillary tangles
    • Neuronal death and brain atrophy
    • Cholinergic projection system withers
  • Senile plaques
    • Extracellular deposits
    • Plaques described as “diffuse”, “neuritic”, or “cored”
    • These may represent different ages of plaque
    • Neuritic plaques are one of the pathologic criteria for diagnosis of Alzheimer’s disease
    • Composed chiefly of beta amyloid
  • Beta amyloid
    • Beta amyloid is a 39-43 amino acid peptide
    • Derived from 700 amino acid amyloid precursor protein (APP)
    • APP may be processed to “amyloidogenic” or “non-amyloidogenic” pathways
  •  -Amyloid Plaques SIGMA-ALDRICH
  • Neurofibrillary tangles
    • Intracellular inclusion
    • Chief component is hyper-phosphorylated tau
    • Tau is a normal intracellular protein which stabilizes microtubules
  • Alzheimer’s pathology
    • Amyloid plaques
    • Neurofibrillary tangles
    • Neuronal death and brain atrophy
    • Cholinergic projection system withers
  • Alzheimer’s disease: genetic risk factors (autosomal dominant)
    • Amyloid precursor protein
    • Presenilin-1
    • Presenilin-2
  • Alzheimer’s disease: genetic risk factors (sporadic)
    • Apolipoprotein E
      • Alleles: E2, E3, E4
      • E4 is present in 15% of population
      • E4 is present in 45-50% of Alzheimer’s
  • Alzheimer’s disease: environmental risk factors
    • Low educational attainment
    • Head injury
    • Depression
    • Vascular risk factors (HTN, DM, hypercholesterolemia)
  • Alzheimer’s disease: stories re pathogenesis
    • Braak staging (“tau hypothesis”?)
    • Amyloid hypothesis
    • Cholinergic hypothesis
  • Braak staging
    • Based on the predictable spread of tangle pathology
      • First entorhinal cortex
      • Then entorhinal cortex + hippocampus
      • Then entorhinal cortex + hippocampus + association cortex
  • Braak staging of AD *(Kaye et al 1997, Silbert et al 2003) AD-type dementia Isolated memory loss (“MCI”) Healthy aging Clinical status Same as above Same as above Same as above Atrophy on MRI* Entorhinal + hippocampus + cortex Entorhinal + hippocampus Entorhinal cortex Tangle histology Braak 5-6 Braak 3-4 Braak 1-2
  • Amyloid hypothesis of AD
    • Holds that neurotoxicity of beta amyloid drives the neurodegenerative process
    • But:
      • beta amyloid is produced under physiologic conditions--how could it be toxic?
  • Merlini and Bellotti, NEJM 349:583-596, 2003
  • Merlini and Bellotti, NEJM 349:583-596, 2003
  • Evaluating the amyloid hypothesis-pros and cons
    • Clinicopathologic correlation
    • Genetics of AD
    • Cell culture studies
    • Animal studies
  • Pathologic correlates of dementia severity (Terry, 1991)
    • Amyloid plaques: poor
    • Neurofibrillary tangles: better
    • Neuronal loss: same as tangles
    • Synaptic density: best
    • So…..clin-path studies do not support the amyloid hypothesis
  • Evaluating the amyloid hypothesis-pros and cons
    • Genetics of AD------------------pro
      • Autosomal dominant AD associated with mutations in amyloid precursor protein (APP)
      • Trisomy 21 also associated with over-expression of APP and AD
      • “ presenilin” initially identified in autosomal dominant AD, since shown to be a component of gamma secretase-- enzyme which processes APP to beta amyloid
  • Evaluating the amyloid hypothesis-pros and cons
    • Clinicopathologic correlation--con
    • Genetics of AD------------------pro
    • Cell culture studies--------------pro
    • Animal studies-------------------+/-
  • Cholinergic hypothesis of AD
    • Based in part on clin-path observation of correlation between cholinergic markers and dementia severity
  • Other putative mechanisms:
    • Inflammation
    • Oxidative damage
    • Ubiquitin-proteasome dysfunction
    • Mitochondrial dysfunction
    • Metal dyshomeostasis (copper, iron)
    • Excitotoxicity
    • Axonal transport dysfunction
  • Treatments available for AD
    • Clinical trials of multiple cholinergic agents have shown enough efficacy to be FDA-approved, but none is dramatically effective
    • Anti-amyloid therapies are in Phase 3 trials
    • Anti-tau therapies are in earlier trials
    • Gene therapy with NGF is also under way targeting the cholinergic system
  • Parkinson’s disease-clinical
    • Cardinal signs:
      • Tremor
      • Rigidity
      • bradykinesia
      • Gait impairment
  • Parkinson’s-clinical
    • Traditionally considered purely a disorder of movement
    • Now appreciated to include autonomic nervous system dysfunction (before motor impairment) and cognitive dysfunction (after motor impairment)
  • Parkinson’s disease pathology
  • Parkinson’s pathology: Lewy bodies
    • Intraneuronal inclusions comprised of alpha synuclein and other proteins
    • Initially thought to be confined to substantia nigra and other projection systems that deteriorate in PD
    • Subsequently identified throughout the nervous system, from brainstem to cortex
    • Incidental Lewy bodies seen in as many as 7-10% of asymptomatic individuals over age 60
  • Parkinson’s genetic risk factors
    • “familial cases are on record, but the evidence is rather unsubstantial…” Adams and Victor 1985
    • “Though there is no evidence to indicate a hereditary factor, a familial evidence is claimed by some.” Merritt’s Textbook of Neurology, 1984
  • Parkinson’s genetic risk factors
  • But..despite the number of genes implicated in rare sub-types of PD, Most cases of “garden-variety” PD are not explained by genes (as in AD)
  • Parkinson’s: environmental risk factors
    • Age
    • Male gender
    • Rural living
    • Smoking is protective
  • Parkinson’s pathogenesis: Braak staging suggests a progressive “synuclein-opathy”:
    • Lewy bodies spread caudal-->rostral
    • Stage 1-2: Lewy bodies in medulla and olfactory bulb (asymptomatic)
    • Stage 3-4: Lewy bodies in substantia nigra, locus coeruleus, cholinergic basal forebrain (parkinson’s symptoms appear when >80% of nigral neurons gone))
    • Stage 5-6: Lewy bodies in forebrain (dementia)
  • Parkinson’s pathogenesis: other models:
    • MPTP model
      • Gives rise to selective neuronal death and parkinsonism, but no Lewy bodies
    • Rotenone model (Greenamyre)
      • Chronic intravenous infusion of mitochondrial complex I inhibitor in rats
      • Produces selective neuronal death, parkinsonism, and Lewy bodies
  • Parkinson’s treatments:
    • Dopaminergic therapy has dramatic symptomatic effects
    • Surgical therapies--both ablative and deep brain stimulator therapies have symptomatic effects
    • Gene therapy with trophic factors is under investigation
    • No proven neuroprotectant therapy to date
  • Frontotemporal dementia-clinical
    • Presents as personality change and disinhibition, in the absence of significant memory loss
    • Also may present as a primary disorder of language
    • Progresses to a more generalized dementia over time
  • Frontotemporal dementia-pathology
    • Clinical syndrome with a variety of underlying pathologies (Pick’s disease, “DLDH”, others)
    • Many have neurofibrillary tangles
  • Frontotemporal dementia-genetics
    • Most cases of FTD are sporadic
    • A mutation in the tau protein is a cause of FTD in a minority of cases (FTDP=17).
    • Tau is a normal intracellular protein which stabilizes microtubules.
  • FTD-treatment
    • Nothing available
  • Amyotrophic lateral sclerosis-clinical
    • Also known as “motor neuron disease” or “Lou Gehrig’s disease”
    • Presents as slowly progressive weakness and muscle wasting.
    • Death within 2-5 years in most patients due to respiratory failure
    • Concomitant FTD in a sub-population of patients (subclinical neuropsych changes may be more common)
  • ALS-pathology
  • ALS-genetics
    • About 10% of cases are familial
    • About 2-3% are caused by mutations in Cu/Zn SOD
  • ALS-treatment
    • Riluzole, a glutamate antagonist, prolongs survival by a few months
    • Treatment trials with trophic factors have failed
    • No other symptomatic or neuroprotectant therapy
    • No SOD-directed therapy
  • Spinocerebellar ataxia-clinical
    • Slowly progressive gait disorder, slurred speech, and clumsiness
    • Age of onset widely variable--from early childhood to late life
    • Patients look like they are intoxicated with alcohol
  • Spinocerebellar ataxia-pathology
  • Spinocerebellar ataxia-genetics (autosomal dominant) How and why does a polyglutamine repeat in several different proteins--give rise to a single phenotype? (there are other phenotypes associated with other polyglutamine repeats)
  • Neurodegeneration-summary Hunting-tin inclusion Caudate, ctx Chorea, dementia HD many Cerebel’r atrophy Cb, SC ataxia SCA SOD MN loss Motor n. weakness ALS tau NFT ctx dementia FTD alphasyn Lewy b. S. nigra motor PD AB, tau Plq, NFT HC, ctx dementia AD protein histology region signs
  • Unanswered questions
    • How does the identification of the deranged protein in each disease explain the selective vulnerability of neurons?
    • Are the mutated proteins themselves neurotoxic? Or what?
    • What can we learn from transgenic mouse models? (examples: APP, tau mutants)
  • Questions?