Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer’s disease

• Published in: Brain (London, England : 1878) England : 1878), 2014-05, Vol.137 (5), p.1533-1549
• Main Authors: Shinohara, Mitsuru, Fujioka, Shinsuke, Murray, Melissa E., Wojtas, Aleksandra, Baker, Matthew, Rovelet-Lecrux, Anne, Rademakers, Rosa, Das, Pritam, Parisi, Joseph E., Graff-Radford, Neill R., Petersen, Ronald C., Dickson, Dennis W., Bu, Guojun
• Format: Article
• Language: English
• Subjects: Adult; Adult and adolescent clinical studies; Aged; Aged, 80 and over; Alzheimer Disease - classification; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases - metabolism; Aspartic Acid Endopeptidases - metabolism; Biological and medical sciences; Brain - metabolism; Brain - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Female; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Humans; Male; Medical sciences; Middle Aged; Nerve Tissue Proteins - metabolism; Nervous system (semeiology, syndromes); Neurofibrillary Tangles - pathology; Neurology; Organic mental disorders. Neuropsychology; Original; Postmortem Changes; Presenilin-1 - genetics; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Synapses - metabolism; Synapses - pathology; tau Proteins - metabolism
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awu046

Sporadic and familial Alzheimer’s disease differ in region-specific amyloid-β accumulation, pattern of neurodegeneration, and symptoms. Shinohara et al. quantify amyloid-β, tau and related molecules and reveal a synapse-associated pattern of amyloid-β42 in sporadic disease, and APP-associated amyloid-β42 in familial cases. Aberrant synaptic processes and APP processing respectively may drive these differences. Recent studies suggest that subcortical structures, including striatum, are vulnerable to amyloid-β accumulation and other neuropathological features in familial Alzheimer’s disease due to autosomal dominant mutations. We explored differences between familial and sporadic Alzheimer’s disease that might shed light on their respective pathogenic mechanisms. To this end, we analysed 12 brain regions, including neocortical, limbic and subcortical areas, from post-mortem brains of familial Alzheimer’s disease (n = 10; age at death: 50.0 ± 8.6 years) with mutations in amyloid precursor protein (APP) or presenilin 1 (PSEN1), sporadic Alzheimer’s disease (n = 19; age at death: 84.7 ± 7.8 years), neurologically normal elderly without amyloid-β accumulation (normal ageing; n = 13, age at death: 82.9 ± 10.8 years) and neurologically normal elderly with extensive cortical amyloid-β deposits (pathological ageing; n = 15; age at death: 92.7 ± 5.9 years). The levels of amyloid-β40, amyloid-β42, APP, apolipoprotein E, the synaptic marker PSD95 (now known as DLG4), the astrocyte marker GFAP, other molecules related to amyloid-β metabolism, and tau were determined by enzyme-linked immunosorbent assays. We observed that familial Alzheimer’s disease had disproportionate amyloid-β42 accumulation in subcortical areas compared with sporadic Alzheimer’s disease, whereas sporadic Alzheimer’s disease had disproportionate amyloid-β42 accumulation in cortical areas compared to familial Alzheimer’s disease. Compared with normal ageing, the levels of several proteins involved in amyloid-β metabolism were significantly altered in both sporadic and familial Alzheimer’s disease; however, such changes were not present in pathological ageing. Among molecules related to amyloid-β metabolism, the regional distribution of PSD95 strongly correlated with the regional pattern of amyloid-β42 accumulation in sporadic Alzheimer’s disease and pathological ageing, whereas the regional distribution of APP as well as β-C-terminal fragment of APP were strongly associated with the regional pattern o