Table 1.
Pathological aggregates in neurodegenerative diseases
| Disease | Proteins that aggregate | Location of aggregates | Brain region(s) affected | Common co-pathologies (% cases where observed) |
|---|---|---|---|---|
| AD | Amyloid beta (Aβ)—plaques and cerebral amyloid angiopathy (CAA) τ-Protein—neurofibrillary tangles (NFTs), neuropil threads (NTs) |
Extracellular with the neuropil (plaques), tunica media and at the basement membrane of cerebral and leptomeningeal blood vessels (CAA) Intracellular within the perikaryon and neuritic cytoplasm of neurons (NFTs, NTs) |
Plaques spread from neocortices to the allocortex and down through the basal ganglia, diencephalon, brain stem and cerebellum NFTs spread from transentorhinal cortex into hippocampus and the neocortex |
TDP-43 cytoplasmic inclusions (over 50% of cases) [71] α-Syn Lewy neurites and LB (over 40% of cases) [150] |
| Tauopathies (FTLD-tau, Pick’s disease, argyrophilic grain disease, frontotemporal dementia with chromosome 17 mutation, NFT-predominant dementia, PSP, CBD, PART) | τ-Protein—NFTs, NTs, Pick bodies, coiled bodies, astrocytic plaques, tufted astrocytes, grains, ballooned neurons | Cytoplasmic (neurons and glia) | Frontal and temporal cortex, basal ganglia, and brain stem | except for argyrophilic grain disease which frequently co-occurs with AD pathology, most cases do not have significant co-pathologies |
| Synucleinopathies (Parkinson’s/DLB/MSA) | α-Syn—LB, Lewy neurites (DLB/PD), glial cytoplasmic inclusions (Papp-Lantos bodies, MSA) | Cytoplasmic [neurons—PD, DLB; oligodendrocytes (Papp-Lantos bodies)—MSA)]; nuclear (neurons—MSA) | Substantia nigra, cortex. In PD, pathology begins in brainstem and spreads up through midbrain to cortex. In DLB, pathology begins in cortex and spreads “down” MSA-P (striato-nigral degeneration with parkinsonism (SDN)): lesions mainly in the striatum and the substantia nigra; gray and white matter pathology MSA-C (olivo-ponto-cerebellar atrophy, OPCA): lesions mainly in the pons, medulla oblongata, and the cerebellum; gray and white matter pathology |
Aβ pathology (over 80% of cases) [61] NFT and NT at Braak stage >II (over 50% of cases) [61] TDP-43 pathology (over 30%) [95] |
| Amyotrophic lateral sclerosis (ALS) | TDP-43, FUS, ubiquilin, C9orf72 translated intronic repeat, SOD1 | Cytoplasmic, nuclear (neurons and oligodendrocytes) | Motor cortex, spinal cord, other cortical regions | Neurofibrillary tangles (78%), atherosclerosis (35%); β-amyloid (35%); tauopathy/tau inclusions (17%), Lewy body formation (11%), microinfarcts (7%), and α-syn (4%) [24] τ- and α-syn pathology in cases of the Kii-Peninsula variant in the temporal lobe, striatum brain stem, cerebellum [82, 102] |
| FTLD-TDP, FTLD-FUS | TDP-43, FUS, ubiquilin, C9orf72 translated intronic repeat | Cytoplasmic, nuclear inclusions in neurons and glial cells | Frontotemporal neocortex and medial temporal lobe |