Lect 2b: AD

Cholinergic Hypothesis (Francis et al 1999)

  • 1970s report -> sig neocortical deficits -> in enzyme responsible for acetylcholine (ACh), choline acetyltransferase (ChAT) synthesis
  • Subsequent discoveries of reduced choline uptake, ACh release & loss of cholinergic perikarya from nucleus basalis of Meynert -> confirmed sig presynaptic cholinergic deficit
  • These studies + emerging role of ACh in learning & memory -> cholinergic hypothesis
  • Hence proposed -> degen of cholinergic neurons in basal forebrain & associated loss of cholinergic neurotransmission in cerebral cortex & other areas -> deterioration in cognitive function
  • Although cholinergic function loss correlates with cognitive impairment in AD -> x mean causal relation.
  • Moreover, a few AD patients -> x sig decreases in ChAT activity, but a small reduction in amygdala
  • Drugs -> effect central cholinergic function -> should improve cognition & behavioural problems
  • 2nd gen ChE inhibitors -> increase monoamine concentrations in cortex after therapeutic dose administration -> influence mood in a +ve manner -> effects hv clinical relevance
  • Donepezil (once daily dosage schedule and produces dose related significant improvements in cognition and global function, with over 80% of patients experiencing improvement/no deterioration in cognition) , rivastigmine
  • Finally, evidence is emerging from clinical trials of cholinomimetic drugs (similar action to ACh) -> improve abnormal non-cognitive behavioural symptoms
  • Hence -> ChE inhibitors -> sig improve manifestations of behaviour disorders -> agitation,
  • Moreover, emerging r/s bet neurotransmission & metabolism of 2 key proteins involved in AD, APP and tau, raises possibility that 2nd gen ChE inhibitors -> alter disease pathology & progression
  • transplantation of ACh rich foetal tissue grafts -> improve cognitive performance of primates -> future possibilities for palliative treatment -> ChE inhibitors most well developed approach

Amyloid cascade hypothesis

  • Cortical plaques -> consist Aβ protein -> produced via processing of its parent protein APP -> gene encoding APP resides on chromosome 21 -> Specific APP physiologic roles x clear -> but contribute to proper neuronal function & cerebral devt
  • (Hardy and Allsop 1991) -> proposed altered APP processing drove Aβ production -> Aβ gave rise to plaques -> plaques induced neurodegeneration -> this neuronal loss -> AD
  • Subsequent research failed to show APP mutation -> a common cause of AD -> but other genetic and molecular research findings -> supported amyloid cascade hypothesis -> specifically, PSEN 1 & 2 mutations -> AD
  • Apolipoprotein E (APOE) alleles influence AD related-markers -> APOE4 allele associates with a younger AD onset & greater lifetime AD risk. The underlying biochemical basis for this association is unknown, but hypotheses abound

  • The mitochondrial cascade hypothesis


  • (Khan, 2004) -> unified explanation -> clinical, biochemical & histologic AD features


  • AD & aging epidemiologically intertwined
  • R/s strength suggests -> these processes share mechanistic commonalities
  • Clinically AD -> x all-or-nothing entity but a continuum
  • Mild, moderate, and severe stages are arbitrarily defined
  • Conversely, more AD phenomena we recognize, the more likely -> AD puzzle come together.

Senile plaques = Amyloid beta

  • peptides of 40 AA -> crucially involved in AD
  • peptides result from the APP -> cleaved by beta secretase and gamma secretase to yield Aβ.
  • Aβ molecules aggregate -> form flexible soluble oligomers which may exist in several forms.
  • γ secretase -> cleaves within the transmembrane region of APP -> gen -> common isoforms -> Aβ40 & Aβ42
  • Aβ40 -> more common
  • Aβ42 -> more fibrillogenic -> so associated with disease
  • APP mutations -> associated with AD -> increased Aβ42 pdn
  • Therapy -> modulate β and γ secretases activity -> prevent Aβ42 pdn

Amyloid beta eqbm

  • monomer to oligomer transition -> initiates Aβ peptide aggregation
  • However -> monomeric state of aggregation-prone peptide -> beyond reach of most experimental techniques & transition lacks understanding
  • Normal equilibrium bet CSF and plasma Aβ -> disrupted with initiation of amyloid deposition
  • Aβ -> Aβ40 & Aβ42 amino acids -> main components of amyloid plaques -> measured in CSF and plasma
  • suggest that the normal equilibrium between CSF and plasma Aβ may be disrupted with the initiation of amyloid deposition in the brain.

Pittsburgh Compound B (PiB) -> imaging of Amyloid beta

  • radioactive analog -> used in positron emission tomography (PET) scans -> image beta-amyloid plaques in neuronal tissue -> provide quantitative information on amyloid deposits in living subjects
  • 1st PiB study -> Henry Engler (2002) -> PET scan -> compound was retained in areas of the cerebral cortex known to contain significant amyloid deposits from post-mortem examinations.
  • Villain N et al (2012) Amyloid beta -> start of disorder ->posterior temporal & parietal lobe then as dementia progresses -> increased PiB in temporal & frontal lobe

Anti-amyloid beta therapy

  • Madani et al 2006


    • Neprilysin -> degrades amyloid beta peptide
    • Neprilysin KO mice -> AD-like behavioral impairment & amyloid-beta deposition in brain -> since rate-limiting step in amyloid beta degradation -> therapeutic target

  • Schenk D (1999) -> Immunization of the transgenic mouse with amyloid beta peptide -> prevented amyloid beta plaque formation


Anti-body mediated clearance

  • Sevigny et al 2016 -> generation of aducanumab, a human monoclonal antibody -> selectively targets aggregated A
  • Prodromal/mild AD patients -> aducanumab reduced brain Aβ -> dose- & time-dependent manner.
  • Slowing of clinical decline measured by Clinical Dementia Rating (MMSE)

Frontotemporal lobar degeneration (FTLD)

  • pathological process -> occurs FTD
  • Characterized by atrophy -> in frontal & temporal lobe of the brain & specific neuronal inclusions
  • Social cognition -> process, store & apply info abt ppl & social situations deteriorates
  • Accumulation of Tau proteins -> brain tissue of 40% FTLD patients -> tau inclusions/“Pick bodies”

Tau

  • Neuronal protein -> binds to microtubules & involved in stabilization of the neuron's 3D structure
  • Neurofibrillary tangles formed -> via hyperphosphorylation of tau protein -> cause aggregation in insoluble form
  • Tau mutations -> reduce binding affinity of tau for microtubules/ increase tau accumulation -> FTD

Tau aggregation inhibitors

  • In future -> biologically selective pharmaceutical agents -> to facilitate the proteolytic degradation of tau aggregates & prevent the further propagation of tau capture in AD

CSF Tau

  • NF tangles marker -> clinical diagnosis use
  • Increased in AD as nerve cells die off  formed tau proteins release contents into CSF
    CSF amyloid beta & Tau
  • AD
    • Decreased Amyloid Beta -> as turned into senile plaques
    • Increased Tau

Tau neuroimaging

  • Limitations of amyloid imaging -> amyloid plaques by themselves -> insufficient for +ve AD diagnosis -> Tau-PET tracer -> complimentary tool to aid in affirmative diagnosis & disease staging


  • 18f-av 1451 -> PET tracer in development for assessment of neurofibrillary tau pathology.

  • Ossenkoppele et al (2016) uptake -> showed distinct AD phenotypes

Prion like spread

  • Misfolding & aggregation of specific proteins within NS -> most age-associated neurodegen diseases (AD) -> classified as protein misfolding disease -> share key biophysical and biochemical characteristics with prion diseases.
  • Prion-like mechanisms in the progression -> Aβ & tau -> induced to misfold and self-assemble -> lesion caused by the pathogenic agents -> spread -> cell-to-cell transportation, including release of intracellular seeds by donor cell & intercellular transport.
  • This hypothesis -> new therapeutic strategies -> for AD -> pre-symptomatic phase

  • Transynaptic spread via exosomes



    • Exosome trf -> small amts of amyloid beta & tau aggregate -> lipid bound -> catch onto next cell & trf damaging proteins to next cell
    • Inhibition of exosome spread as therapy