1. sporadic AD familial AD etiology environmental factors, genetic predisposition etiology oligomerization of A 42 and initial (diffuse) A 42 deposits subtle effects of soluble A 42 oligomers on synaptic function inflammatory responses (microglial and astrocytic activation) and amyloid plaque formation progressive synaptic/neuritic injury altered neuronal ionic homoeostasis & oxidative injury aberrant oligomerization and hyperphosphorylation of tau widespread neuronal dysfunction and cell death associated with neurotransmitter deficits dementia and neurodegeneration increase in total A production or increase in the A 42/40 ratio subtle changes in A production or clearance mutations in APP or presenilin pathophysiological alterations Fig. 1A chromosome 17-linked FTLD

2. Tauopathies tau-positive mutations in tau cause expression of splice variants or missense mutants affect microtuble binding capacity pathophysiological alterations Fig. 1B Chromosome 17-linked FTLD tau pathology TDP-43 proteinopathies tau-negative, ubiquitin-positive etiology loss of a trophic/protective function TDP-43 pathology cause nonsense mediated PGRN mRNA decay reduced secretion of PGRN missorting of PGRN and degradation impaired axonal transport mutations in progranulin neuropathology

3. sporadic PD familial PD etiology largely unknown environmental factors genetic predisposition degeneration of dopaminergic neurons in the substantia nigra pathophysiological alterations etiology mutations in PD-associated genes autosomal dominant autosomal recessive -synuclein LRRK2 parkin PINK1 DJ-1 oxidative stress mitochondrial dysfunction protein misfolding Fig. 1C

4. Prion diseases PrP Ctm PrP PrP HD cytoPrP PG14PrP PrP Sc neurodegeneration infectious prions neurodegeneration etiology sporadic inherited acquired mutations Fig. 1D

5. Gain of function Loss of function neurotoxic signaling PrP synaptic deficits tau, A, PrP impairment of axonal transport tau pore formation -synuclein defective cellular trafficking -synuclein impairment of proteasomal or lysosomal degradation PrP, -synuclein impairment of synaptic dynamics -synuclein increased vulnerability to stress parkin, DJ-1 loss of trophic support progranulin mitochondrial dysfunction PINK1, parkin neuronal dysfunction and cell death Fig. 2