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Karl Herrup, Ph.D.

– Rutgers University
April 27, 2011
—  Memory
—  Language
—  Spatial perceptions
—  Executive functions
◦  Judgment
◦  Problem solving
—  Behavior
◦  Attention
◦  Depression
◦  Aggression
◦  Apathy
—  Plaques
—  Tangles
—  Synaptic loss
—  Cell loss
◦  Hippocampus
◦  Basal nucleus
◦  Locus coeruleus
◦  Dorsal raphe
◦  …and beyond
—  Chronic inflammation
—  Plaques
◦  Fragments of the
APP protein
—  Tangles
◦  Hyper
phosphorylated tau
—  Synaptic loss
—  Cell loss
—  Inflammation
Genes/Loci

APP
(HC21)

Early-Onset PSEN1
AD Familial (30s-50s) (HC14)

Late-Onset PSEN2
Risk factor genes (HC1)

Trisomy 21
APOE APP Dup.
Sporadic (HC19) (30s-40s)

(80s)
Amyloid Precursor Protein
APP 751/770 KPI insert Aβ
Lipid Bilayer
NH2 COOH
695

APP 670/671 APP 717

Lipid Bilayer
Aβ peptide (40-42aa)

β-Secretase α-Secretase γ-Secretase


(BACE1) ADAM10/17 Multi-Subunit Protease
—  Beta amyloid toxicity?
◦  Site of plaques ≠ site of neurodegeneration
◦  30% of cognitively normal have plaques
◦  Mouse AD models: no neuron death
—  Sporadic AD is not clearly defined
—  Not really a hypothesis if AD is defined as
dementia with plaques
—  Central
problem in AD – plaques define
the disease
◦  Trojanowski: the problem of
multiproteinopathies

—  Can we imagine AD without plaques?


—  Brain structure & function normally
decline with age
—  To get AD add three key steps
◦  1. An initiating injury
◦  2. A chronic inflammation
◦  3. A cellular change-of-state
—  Divide and die: Background
—  After it leaves the ventricular zone a
CNS neuron will never divide again
◦  Force a neuron to divide, it cycles
and dies
◦  Add certain toxins, it cycles and
dies
◦  Block the cycle and you block the
death
—  Neurons in the adult brain can cycle
—  Cycling is tightly linked to disease
—  Includes DNA replication
◦  (but not death – a separate webinar)
—  This represents a profound change in
neuronal biology – a ‘change of state’
—  Cycling: a marker for neurons in stress
—  Neurons at risk for death are ‘cycling’
—  At all stages of the disease

AD hippocampal pyramidal cells Busser et al (1998)



—  Neurons at risk for death show DNA replication
—  Stop short of M-phase

Hippocampal neuron
Alzheimer's disease case

Yang et al (2001)

—  Neuronal cycling matches human anatomy
PCNA NeuN Merge

Frontal cortex - 22 months



Yang, Varvel et al, 2005

—  The progression of cell cycles in the mouse
follows the progression of cell death in AD

Varvel et al. J Clin Invest. (2009) 119:3692


Aβ deposition is correlated with
but mechanistically distinct from
the AD disease process
—  Stopping amyloid deposition will help
◦  Slows the amyloid deposition cycle
◦  Slows inflammation
—  Stopping other things might help as much or
more
—  After disease onset, arresting either amyloid or
inflammation does not matter
—  Anti-tau therapies should be successful
throughout the disease
—  Plaques should be a silver, not a gold-standard for
defining AD

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